The domain within your query sequence starts at position 470 and ends at position 562; the E-value for the SH2 domain shown below is 1.26e-2.

QNGIHGPLMDPFVQAKLWPEDGLYLIQWSTSHLHRLILTVAHRNPAFSNGPRGLRLRKFP
ITQQPGAFVLDGWGRSFASLGDLRLALQGCSLR

SH2

Src homology 2 domains

• SMART accession number: SM00252
• Description: Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.
• Interpro abstract (IPR000980):

  The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps [ (PUBMED:3025655) ]. Similar sequences were later found in many other intracellular signal-transducing proteins [ (PUBMED:1377638) ]. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner [ (PUBMED:7883800) (PUBMED:15335710) (PUBMED:14731533) (PUBMED:7531822) ]. They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates.

  The structure of the SH2 domain belongs to the alpha+beta class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel beta-sheet, flanked by 2 short alpha-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the beta-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins [ (PUBMED:11911873) ].

There are 58927 SH2 domains in 53279 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Cellular role: signalling
Binding / catalysis: phosphotyrosine-containing peptide-binding

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Mandiyan V, Andreev J, Schlessinger J, Hubbard SR
• Crystal structure of the ARF-GAP domain and ankyrin repeats of PYK2-associated protein beta.
• EMBO J. 1999; 18: 6890-8

ADP ribosylation factors (ARFs), which are members of the Ras superfamily of GTP-binding proteins, are critical components of vesicular trafficking pathways in eukaryotes. Like Ras, ARFs are active in their GTP-bound form, and their duration of activity is controlled by GTPase-activating proteins (GAPs), which assist ARFs in hydrolyzing GTP to GDP. PAPbeta, a protein that binds to and is phosphorylated by the non-receptor tyrosine kinase PYK2, contains several modular signaling domains including a pleckstrin homology domain, an SH3 domain, ankyrin repeats and an ARF-GAP domain. Sequences of ARF-GAP domains show no recognizable similarity to those of other GAPs, and contain a characteristic Cys-X(2)-Cys-X(16-17)-Cys-X(2)-Cys motif. The crystal structure of the PAPbeta ARF-GAP domain and the C-terminal ankyrin repeats has been determined at 2.1 A resolution. The ARF-GAP domain comprises a central three-stranded beta-sheet flanked by five alpha-helices, with a Zn(2+) ion coordinated by the four cysteines of the cysteine-rich motif. Four ankyrin repeats are also present, the first two of which form an extensive interface with the ARF-GAP domain. An invariant arginine and several nearby hydrophobic residues are solvent exposed and are predicted to be the site of interaction with ARFs. Site-directed mutagenesis of these residues confirms their importance in ARF-GAP activity.

• Smalla M et al.
• Solution structure of the receptor tyrosine kinase EphB2 SAM domain and identification of two distinct homotypic interaction sites.
• Protein Sci. 1999; 8: 1954-61

The sterile alpha motif (SAM) is a protein interaction domain of around 70 amino acids present predominantly in the N- and C-termini of more than 60 diverse proteins that participate in signal transduction and transcriptional repression. SAM domains have been shown to homo- and hetero-oligomerize and to mediate specific protein-protein interactions. A highly conserved subclass of SAM domains is present at the intracellular C-terminus of more than 40 Eph receptor tyrosine kinases that are involved in the control of axonal pathfinding upon ephrin-induced oligomerization and activation in the event of cell-cell contacts. These SAM domains appear to participate in downstream signaling events via interactions with cytosolic proteins. We determined the solution structure of the EphB2 receptor SAM domain and studied its association behavior. The structure consists of five helices forming a compact structure without binding pockets or exposed conserved aromatic residues. Concentration-dependent chemical shift changes of NMR signals reveal two distinct well-separated areas on the domains' surface sensitive to the formation of homotypic oligomers in solution. These findings are supported by analytical ultracentrifugation studies. The conserved Tyr932, which was reported to be essential for the interaction with SH2 domains after phosphorylation, is buried in the hydrophobic core of the structure. The weak capability of the isolated EphB2 receptor SAM domain to form oligomers is supposed to be relevant in vivo when the driving force of ligand binding induces receptor oligomerization. A formation of SAM tetramers is thought to provide an appropriate contact area for the binding of a low-molecular-weight phosphotyrosine phosphatase and to initiate further downstream responses.

• Stapleton D, Balan I, Pawson T, Sicheri F
• The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization.
• Nat Struct Biol. 1999; 6: 44-9

The sterile alpha motif (SAM) domain is a novel protein module of approximately 70 amino acids that is found in a variety of signaling molecules including tyrosine and serine/threonine protein kinases, cytoplasmic scaffolding and adaptor proteins, regulators of lipid metabolism, and GTPases as well as members of the ETS family of transcription factors. The SAM domain can potentially function as a protein interaction module through the ability to homo- and hetero-oligomerize with other SAM domains. This functional property elicits the oncogenic activation of chimeric proteins arising from translocation of the SAM domain of TEL to coding regions of the betaPDGF receptor, Abl, JAK2 protein kinase and the AML1 transcription factor. Here we describe the 2.0 A X-ray crystal structure of a SAM domain homodimer from the intracellular region of the EphA4 receptor tyrosine kinase. The structure reveals a mode of dimerization that we predict is shared amongst the SAM domains of the Eph receptor tyrosine kinases and possibly other SAM domain containing proteins. These data indicate a mechanism through which an independently folding protein module can form homophilic complexes that regulate signaling events at the membrane and in the nucleus.

• Thanos CD, Goodwill KE, Bowie JU
• Oligomeric structure of the human EphB2 receptor SAM domain.
• Science. 1999; 283: 833-6

The sterile alpha motif (SAM) domain is a protein interaction module that is present in diverse signal-transducing proteins. SAM domains are known to form homo- and hetero-oligomers. The crystal structure of the SAM domain from an Eph receptor tyrosine kinase, EphB2, reveals two large interfaces. In one interface, adjacent monomers exchange amino-terminal peptides that insert into a hydrophobic groove on each neighbor. A second interface is composed of the carboxyl-terminal helix and a nearby loop. A possible oligomer, constructed from a combination of these binding modes, may provide a platform for the formation of larger protein complexes.

• Whisstock JC, Lesk AM
• SH3 domains in prokaryotes.
• Trends Biochem Sci. 1999; 24: 132-3

• Barford D, Neel BG
• Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2.
• Structure. 1998; 6: 249-54

The crystal structure of the protein tyrosine phosphatase SHP-2 reveals the mechanism of auto-inhibition of phosphatase activity by its SH2 domains. Phosphotyrosine peptide stimulation of the phosphatase activity, resulting from peptide binding to the N-terminal SH2 domain, is linked to conformational changes within the protein, including an unprecedented allosteric transition of the N-terminal SH2 domain.

• Sticht H, Pickford AR, Potts JR, Campbell ID
• Solution structure of the glycosylated second type 2 module of fibronectin.
• J Mol Biol. 1998; 276: 177-87

Fibronectin is an extracellular matrix glycoprotein that plays a role in a number of physiological processes involving cell adhesion and migration. The modules of the fibronectin monomer are organized into proteolytically resistant domains that in isolation retain their affinity for various ligands. The tertiary structure of the glycosylated second type 2 module (2F2) from the gelatin-binding domain of fibronectin was determined by two-dimensional nuclear magnetic resonance spectroscopy and simulated annealing. The structure is well defined with an overall fold typical of F2 modules, showing two double-stranded antiparallel beta-sheets and a partially solvent-exposed hydrophobic cluster. An N-terminal beta-sheet, that was not present in previously determined F2 module structures, may be important for defining the relative orientation of adjacent F2 modules in fibronectin. This is the first three-dimensional structure of a glycosylated module of fibronectin, and provides insight into the possible role of the glycosylation in protein stability, protease resistance and modulation of collagen binding. Based on the structures of the isolated modules, models for the 1F22F2 pair were generated by randomly changing the orientation of the linker peptide between the modules. The models suggest that the two putative collagen binding sites in the pair form discrete binding sites, rather than combining to form a single binding site.

• Williams JC, Wierenga RK, Saraste M
• Insights into Src kinase functions: structural comparisons.
• Trends Biochem Sci. 1998; 23: 179-84

Recent structures of Src tyrosine kinases reveal complex mechanisms for regulation of enzymatic activity. The regulatory SH3 and SH2 domains bind to the back of the catalytic kinase domain via a linker region that joins the SH2 domain to the catalytic domain. Members of a subgroup of the Src kinase family show distinct features in this linker and in the loops that interact with it. Hydrophobicity of key residues in this region is important for intramolecular regulation. The kinases Abl, Btk and Csk seem to have the same molecular architecture as Src. Structural comparisons between serine/threonine and tyrosine kinases indicate a specific twisting mechanism involving the N- and C-terminal lobes of the catalytic domain. This motion could provide insights into the various mechanisms used to regulate kinase activity.

• Arold S et al.
• The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling.
• Structure. 1997; 5: 1361-72

BACKGROUND: Human immunodeficiency virus (HIV) Nef protein accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases. The structures of free Nef and Nef bound to Src homology region 3 (SH3) domain are important for the elucidation of how the affinity and specificity for the Src kinase family SH3 domains are achieved, and also for the development of potential drugs and vaccines against AIDS. RESULTS: We have determined the crystal structures of the conserved core of HIV-1 Nef protein alone and in complex with the wild-type SH3 domain of the p59fyn protein tyrosine kinase (Fyn), at 3.0 A resolution. Comparison of the bound and unbound Nef structures revealed that a proline-rich motif (Pro-x-x-Pro), which is implicated in SH3 binding, is partially disordered in the absence of the binding partner; this motif only fully adopts a left-handed polyproline type II helix conformation upon complex formation with the Fyn SH3 domain. In addition, the structures show how an arginine residue (Arg77) of Nef interacts with Asp 100 of the so-called RT loop within the Fyn SH3 domain, and triggers a hydrogen-bond rearrangement which allows the loop to adapt to complement the Nef surface. The Arg96 residue of the Fyn SH3 domain is specifically accommodated in the same hydrophobic pocket of Nef as the isoleucine residue of a previously described Fyn SH3 (Arg96-->lle) mutant that binds to Nef with higher affinity than the wild type. CONCLUSIONS: The three-dimensional structures support evidence that the Nef-Fyn complex forms in vivo and may have a crucial role in the T cell perturbating action of Nef by altering T cell receptor signaling. The structures of bound and unbound Nef reveal that the multivalency of SH3 binding may be achieved by a ligand induced flexibility in the RT loop. The structures suggest possible targets for the design of inhibitors which specifically block Nef-SH3 interactions.

• Barrett T et al.
• The structure of the GTPase-activating domain from p50rhoGAP.
• Nature. 1997; 385: 458-61

Members of the Rho family of small G proteins transduce signals from plasma-membrane receptors and control cell adhesion, motility and shape by actin cytoskeleton formation. They also activate other kinase cascades. Like all other GTPases, Rho proteins act as molecular switches, with an active GTP-bound form and an inactive GDP-bound form. The active conformation is promoted by guanine-nucleotide exchange factors, and the inactive state by GTPase-activating proteins (GAPs) which stimulate the intrinsic GTPase activity of small G proteins. Rho-specific GAP domains are found in a wide variety of large, multi-functional proteins. Here we report the crystal structure of an active 242-residue C-terminal fragment of human p50rhoGAP. The structure is an unusual arrangement of nine alpha-helices, the core of which includes a four-helix bundle. Residues conserved across the rhoGAP family are largely confined to one face of this bundle, which may be an interaction site for target G proteins. In particular, we propose that Arg 85 and Asn 194 are involved in binding G proteins and enhancing GTPase activity.

• Carugo KD, Banuelos S, Saraste M
• Crystal structure of a calponin homology domain.
• Nat Struct Biol. 1997; 4: 175-9

The three-dimensional structure of the calponin homology domain present in many actin binding cytoskeletal and signal-transducing proteins has been determined at 2.0 A resolution.

• Konrat R, Weiskirchen R, Krautler B, Bister K
• Solution structure of the carboxyl-terminal LIM domain from quail cysteine-rich protein CRP2.
• J Biol Chem. 1997; 272: 12001-7

Proteins of the cysteine-rich protein (CRP) family (CRP1, CRP2, and CRP3) are implicated in diverse processes linked to cellular differentiation and growth control. CRP proteins contain two LIM domains, each formed by two zinc-binding modules of the CCHC and CCCC type, respectively. The solution structure of the carboxyl-terminal LIM domain (LIM2) from recombinant quail CRP2 was determined by multidimensional homo- and heteronuclear magnetic resonance spectroscopy. The folding topology retains both independent zinc binding modules (CCHC and CCCC). Each module consists of two orthogonally arranged antiparallel beta-sheets, and the carboxyl-terminal CCCC module is terminated by an alpha-helix. 15N magnetic relaxation data indicate that the modules differ in terms of conformational flexibility. They pack together via a hydrophobic core region. In addition, Arg122 in the CCHC module and Glu155 in the CCCC module are linked by an intermodular hydrogen bond and/or salt bridge. These residues are absolutely conserved in the CRP family of LIM proteins, and their interaction might contribute to the relative orientation of the two zinc-binding modules in CRP LIM2 domains. The global fold of quail CRP2 LIM2 is very similar to that of the carboxyl-terminal LIM domain of the related but functionally distinct CRP family member CRP1, analyzed recently. The carboxyl-terminal CCCC module is structurally related to the DNA-binding domain of the erythroid transcription factor GATA-1. In the two zinc-binding modules of quail CRP2 LIM2, flexible loop regions made up of conserved amino acid residues are located on the same side of the LIM2 domain and may cooperate in macromolecular recognition.

• Kuriyan J, Cowburn D
• Modular peptide recognition domains in eukaryotic signaling.
• Annu Rev Biophys Biomol Struct. 1997; 26: 259-88

A characteristic feature of cellular signal transduction pathways in eukaryotes is the separation of catalysis from target recognition. Several modular domains that recognize short peptide sequences and target signaling proteins to these sequences have been identified. The structural bases of the specificities of recognition by SH2, SH3, and PTB domains have been elucidated by X-ray crystallography and NMR, and these results are reviewed here. In addition, the mechanism of cooperative interactions between these domains is discussed.

• Liepinsh E, Ilag LL, Otting G, Ibanez CF
• NMR structure of the death domain of the p75 neurotrophin receptor.
• EMBO J. 1997; 16: 4999-5005

The intracellular domain of the p75 neurotrophin receptor (p75ICD) lacks catalytic activity but contains a motif similar to death domains found in the cytoplasmic regions of members of the tumor necrosis factor receptor family and their downstream targets. Although some aspects of the signaling pathways downstream of p75 have been elucidated recently, mechanisms of receptor activation and proximal signaling events are unknown. Here we report the nuclear magnetic resonance (NMR) structure of the 145 residue long p75ICD. The death domain of p75ICD consists of two perpendicular sets of three helices packed into a globular structure. The polypeptide segment connecting the transmembrane and death domains as well as the serine/threonine-rich C-terminal end are highly flexible in p75ICD. Unlike the death domains involved in signaling by the TNF receptor and Fas, p75ICD does not self-associate in solution. A surface area devoid of charged residues in the p75ICD death domain may indicate a potential site of interaction with downstream targets.

• Sicheri F, Moarefi I, Kuriyan J
• Crystal structure of the Src family tyrosine kinase Hck.
• Nature. 1997; 385: 602-9

The crystal structure of the haematopoietic cell kinase Hck has been determined at 2.6/2.9 A resolution. Inhibition of enzymatic activity is a consequence of intramolecular interactions of the enzyme's Src-homology domains SH2 and SH3, with concomitant displacement of elements of the catalytic domain. The conformation of the active site has similarities with that of inactive cyclin-dependent protein kinases.

• Xu W, Harrison SC, Eck MJ
• Three-dimensional structure of the tyrosine kinase c-Src.
• Nature. 1997; 385: 595-602

The structure of a large fragment of the c-Src tyrosine kinase, comprising the regulatory and kinase domains and the carboxy-terminal tall, has been determined at 1.7 A resolution in a closed, inactive state. Interactions among domains, stabilized by binding of the phosphorylated tail to the SH2 domain, lock the molecule in a conformation that simultaneously disrupts the kinase active site and sequesters the binding surfaces of the SH2 and SH3 domains. The structure shows how appropriate cellular signals, or transforming mutations in v-Src, could break these interactions to produce an open, active kinase.

• Zhang ZY
• Structure, mechanism, and specificity of protein-tyrosine phosphatases.
• Curr Top Cell Regul. 1997; 35: 21-68

• Lee CH, Saksela K, Mirza UA, Chait BT, Kuriyan J
• Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain.
• Cell. 1996; 85: 931-42

The crystal structure of the conserved core of HIV-1 Nef has been determined in complex with the SH3 domain of a mutant Fyn tyrosine kinase (a single amino acid substitution, Arg-96 to isoleucine), to which Nef binds tightly. The conserved PxxP sequence motif of Nef, known to be important for optimal viral replication, is part of a polyproline type II helix that engages the SH3 domain in a manner resembling closely the interaction of isolated peptides with SH3 domains. The Nef-SH3 structure also reveals how high affinity and specificity in the SH3 interaction is achieved by the presentation of the PxxP motif within the context of the folded structure of Nef.

• Metzler WJ, Leiting B, Pryor K, Mueller L, FarmerBT2nd
• The three-dimensional solution structure of the SH2 domain from p55blk kinase.
• Biochemistry. 1996; 35: 6201-11

Signal transduction in B cells is mediated, in part, by the interaction of the cytoplasmic components of the antigen receptor complex and various members of the src family tyrosine kinases. Key to this process appears to be the interaction of the tyrosine kinase SH2 domains with the tyrosine-phosphorylated cytoplasmic domain of Ig-alpha, a disulfide-bonded heterodimeric (with Ig-beta or Ig-gamma) transmembrane protein that noncovalently associates with the antigen receptor immunoglobin chains. In addition to binding to the phosphorylated cytoplasmic domains of Ig-alpha and Ig-beta, blk and fyn(T), two members of the src family kinases, have been shown to bind overlapping but distinct sets of phosphoproteins [Malek & Desiderio (1993) J. Biol. Chem. 268. 22557-22565]. A comparison of their three-dimensional structures may elucidate the apparently subtle differences required for phosphoprotein discrimination. To begin characterizing the blk/fyn/phosphosphoprotein interactions, we have determined the three-dimensional solution structure of the SH2 domain of blk kinase by nuclear magnetic resonance (NMR) spectroscopy. 1H, 13C, and 15N resonances of the SH2 domain of blk kinase were assigned by analysis of multidimensional, double- and triple-resonance NMR experiments. Twenty structures of the blk SH2 domain were refined with the program X-PLOR using a total of 2080 experimentally derived conformational restraints. The structures converged to a root-mean-squared (rms) distance deviation of 0.51 and 0.95 A for the backbone atoms and for the non-hydrogen atoms, respectively. The blk SH2 domain adopts the prototypical SH2 fold. Structurally, blk SH2 is most similar to the crystal structure of the v-src SH2 domain [Waksman et al. (1993) Nature 358.646-653] and superimposes on the crystal structure with an rmsd of 1.52 A for the backbone atoms. The largest deviations occur in the four loops interconnecting beta-strands A-E, which are the least well-defined regions in the NMR structure. Exclusion of these loops lowers this rmsd to 0.82 A. The conformation of the BC loop in the blk SH2 domain is similar to the open conformation in the apo lck SH2 domain, suggesting that, like the lck SH2 domain, the blk SH2 domain may have a gated phosphopeptide binding site. Finally, it is proposed that the amino acid substitution of Lys 88 (blk) for Glu [fyn(T)] is important for the observed differences in specificity between blk and fyn(T) SH2 domains.

• Thornton KH, Mueller WT, McConnell P, Zhu G, Saltiel AR, Thanabal V
• Nuclear magnetic resonance solution structure of the growth factor receptor-bound protein 2 Src homology 2 domain.
• Biochemistry. 1996; 35: 11852-64

A family of NMR solution structures of the growth factor receptor-bound protein 2 (Grb2) SH2 domain has been determined by heteronuclear multidimensional NMR. Proton, nitrogen, and carbon chemical shift assignments have been made for the SH2 domain of Grb2. Assignments were made from a combination of homonuclear two-dimensional and 15N- and 13C-edited three-dimensional spectra at pH 6.2 and 298 K. Structure-induced proton and carbon secondary shifts were calculated and used to facilitate the spectral assignment process. NOE, scalar coupling, secondary chemical shift, and amide proton exchange data were used to characterize the secondary structural elements and hydrogen-bonding network in the Grb2 SH2 domain. The three-dimensional structure of the Grb2 SH2 domain was calculated using 1112 restraints obtained from NOE, coupling constant, and amide proton exchange data. The rmsd for the 24 calculated structures to the mean structure of the Grb2 SH2 domain was 0.75 A for backbone and 1.28 A for all heavy atoms. The three-dimensional fold of the Grb2 SH2 domain is similar to that observed for other SH2 domains and consists of two alpha-helical segments and eight beta-strands, six strands that make up two contiguous antiparallel beta-sheets, and two strands that form two short parallel beta-sheets. The structure of the phosphotyrosine binding pocket of Grb2 is similar to that observed for other SH2 domains. The hydrophobic binding pocket of Grb2 is similar to that observed for Src with the exception that tryptophan 121 of Grb2 occupies part of the pY+3 binding pocket. Structural implications for the Grb2 SH2 domain selectivity at the pY+2 and pY+3 sites are discussed.

• Worthington MT, Amann BT, Nathans D, Berg JM
• Metal binding properties and secondary structure of the zinc-binding domain of Nup475.
• Proc Natl Acad Sci U S A. 1996; 93: 13754-9

Nup475 is a nuclear zinc-binding protein of unknown function that is induced in mammalian cells by growth factor mitogens. Nup475 contains two tandemly repeated sequences YKTELCX8CX5CX3H (Cys3His repeats) that are thought to be zinc-bindin domains. Similar sequences have been found in a number of proteins from various species of eukaryotes. To determine the metal binding properties and secondary structure of the putative zinc-binding domains of Nup475, we have used synthetic or recombinant peptides that contain one or two domain sequences. The peptide with a single domain bound 1.0 +/- 0.1 equivalents of Co2+, and the peptide with two domains bound 1.7 +/- 0.4 equivalents of Co2+. Both peptides bound Co2+ and Zn2+ with affinities similar to those of classical zinc finger peptides. In each case, the Co2+ complex exhibited strong d-d transitions characteristic of tetrahedral coordination. For structural studies by nuclear magnetic resonance spectroscopy, we used a more soluble two-domain peptide that had a single amino acid substitution in a nonconserved amino acid residue in the second Cys3His repeat. The mutant peptide unexpectedly showed loss of one of its metal binding sites and displayed ordered structure for only the first Cys3His sequence. On the basis of the nuclear magnetic resonance data, we propose a structure for the Nup475 metal-binding domain in which the zinc ion is coordinated by the conserved cysteines and histidine, and the conserved YKTEL motif forms a parallel sheet-like structure with the C terminus of this domain. This structure is unlike that of any previously described class of metal binding domain.

• Bork P, Margolis B
• A phosphotyrosine interaction domain.
• Cell. 1995; 80: 693-4

• Jia Z, Barford D, Flint AJ, Tonks NK
• Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B.
• Science. 1995; 268: 1754-8

The crystal structures of a cysteine-215-->serine mutant of protein tyrosine phosphatase 1B complexed with high-affinity peptide substrates corresponding to an autophosphorylation site of the epidermal growth factor receptor were determined. Peptide binding to the protein phosphatase was accompanied by a conformational change of a surface loop that created a phosphotyrosine recognition pocket and induced a catalytically competent form of the enzyme. The phosphotyrosine side chain is buried within the period and anchors the peptide substrate to its binding site. Hydrogen bonds between peptide main-chain atoms and the protein contribute to binding affinity, and specific interactions of acidic residues of the peptide with basic residues on the surface of the enzyme confer sequence specificity.

• Kavanaugh WM, Turck CW, Williams LT
• PTB domain binding to signaling proteins through a sequence motif containing phosphotyrosine.
• Science. 1995; 268: 1177-9

Src homology 2 (SH2) domains mediate assembly of signaling complexes by binding specifically to tyrosine-phosphorylated proteins. A phosphotyrosine binding (PTB) domain has been identified which also binds specifically to tyrosine-phosphorylated targets, but is structurally different from SH2 domains. Expression cloning was used to identify targets of PTB domains. PTB domains bound to phosphotyrosine within a sequence motif, asparagine-X1-X2-phosphotyrosine (where X represents any amino acid), that is found in many signaling proteins and is not recognized by SH2 domains. Mutational studies indicated that high affinity binding of PTB domains may require a specific conformation of the motif.

• Maignan S, Guilloteau JP, Fromage N, Arnoux B, Becquart J, Ducruix A
• Crystal structure of the mammalian Grb2 adaptor.
• Science. 1995; 268: 291-3

The mammalian growth factor receptor-binding protein Grb2 is an adaptor that mediates activation of guanine nucleotide exchange on Ras. Grb2 binds to the receptor through its SH2 domain and to the carboxyl-terminal domain of Son of sevenless through its two SH3 domains. It is thus a key element in the signal transduction pathway. The crystal structure of Grb2 was determined to 3.1 angstrom resolution. The asymmetric unit is composed of an embedded dimer. The interlaced junctions between the SH2 and SH3 domains bring the two adjacent faces of the SH3 domains in van der Waals contact but leave room for the binding of proline-rich peptides.

• Mikol V, Baumann G, Zurini MG, Hommel U
• Crystal structure of the SH2 domain from the adaptor protein SHC: a model for peptide binding based on X-ray and NMR data.
• J Mol Biol. 1995; 254: 86-95

Src homology 2 domains (SH2) are protein molecules found within a wide variety of cytoplasmic signalling molecules that bind with high affinity to phosphotyrosyl (pY)-containing protein sequences. We report here for crystal structure of the SH2 domain from the adaptor protein SHC (Shc), which has been refined by restrained least-squares methods to an R-factor of 17.3% to 2.7 A. The overall Shc architecture is essentially similar to that determined in other SH2 domains but it shows significant differences in a number of loops, thus providing a molecular surface with no obvious secondary pocket. Based on the knowledge of the crystal structure of the protein a model for a low affinity Shc-bound peptide has been generated from nuclear magnetic resonance data in solution using transferred nuclear Overhauser enhancements as intramolecular distance restraints. The model shows that the tyrosine moiety binds Shc in a rather similar way to that observed for other SH2-peptide complexes, but that the residue in position +3 does not seem to make specific contact with the protein. An intermolecular crystallographic interaction occurs between the pY-binding site and the C-terminal residues of a symmetry-related molecule. This crystal packing interaction suggests how inhibitory regulation could play a role in SHC activity.

• Narula SS et al.
• Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide.
• Structure. 1995; 3: 1061-73

BACKGROUND: Recruitment of the intracellular tyrosine kinase Syk to activated immune-response receptors is a critical early step in intracellular signaling. In mast cells, Syk specifically associates with doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) that are found within the IgE receptor. The mechanism by which Syk recognizes these motifs is not fully understood. Both Syk SH2 (Src homology 2) domains are required for high-affinity binding to these motifs, but the C-terminal SH2 domain (Syk-C) can function independently and can bind, in isolation, to the tyrosine-phosphorylated IgE receptor in vitro. In order to improve understanding of the cellular function of Syk, we have determined the solution structure of Syk-C complexed with a phosphotyrosine peptide derived from the gamma subunit of the IgE receptor. RESULTS: The Syk-C:peptide structure is compared with liganded structures of both the SH2 domain of Src and the C-terminal SH2 domain of ZAP-70 (the 70 kDa zeta-associated protein). The topologies of these domains are similar, although significant differences occur in the loop regions. In the Syk-C structure, the phosphotyrosine and leucine residues of the peptide ligand interact with pockets on the protein, and the intervening residues are extended. CONCLUSIONS: Syk-C resembles other SH2 domains in its peptide-binding interactions and overall topology, a result that is consistent with its ability to function as an independent SH2 domain in vitro. This result suggests that Syk-C plays a unique role in the intact Syk protein. The determinants of the binding affinity and selectivity of Syk-C may reside in the least-conserved structural elements that comprise the phosphotyrosine- and leucine-binding sites. These structural features can be exploited for the design of Syk-selective SH2 antagonists for the treatment of allergic disorders and asthma.

• Ponting CP
• SAM: a novel motif in yeast sterile and Drosophila polyhomeotic proteins.
• Protein Sci. 1995; 4: 1928-30

Single copies of an approximately 65-70 residue domain are shown to be present in the sequences of 14 eukaryotic proteins, including yeast byr2, STE11, ste4, and STE50, which are essential participants in sexual differentiation. This domain, named SAM (sterile alpha motif), appears to participate in other developmental processes because it is also present in Drosophila polyhomeotic gene product and related homologues, which are thought to regulate determination of segmental specification in early embryogenesis. Its appearance in byr2 and STE11, which are MEK kinases, and in proteins containing pleckstrain homology, src homology 3, and discs-large homologous region domains, suggests possible participation in signal transduction pathways.

• Trub T et al.
• Specificity of the PTB domain of Shc for beta turn-forming pentapeptide motifs amino-terminal to phosphotyrosine.
• J Biol Chem. 1995; 270: 18205-8

Shc phosphorylation in cells following growth factor, insulin, cytokine, and lymphocyte receptor activation leads to its association with Grb2 and activation of Ras. In addition to being a cytoplasmic substrate of tyrosine kinases, Shc contains an SH2 domain and a non-SH2 phosphotyrosine binding (PTB) domain. Here we show that the Shc PTB domain, but not the SH2 domain, binds with high affinity (ID50 approximately equal to 1 microM) to phosphopeptides corresponding to the sequence surrounding Tyr250 of the polyoma virus middle T (mT) antigen (LLSNPTpYSVMRSK). Truncation studies show that five residues amino-terminal to tyrosine are required for high affinity binding, whereas all residues carboxyl-terminal to tyrosine can be deleted without loss of affinity. Substitution studies show that tyrosine phosphorylation is required and residues at -5, -3, -2, and -1 positions relative to pTyr are important for this interaction. 1H NMR studies demonstrate that the phosphorylated mT antigen-derived sequence forms a stable beta turn in solution, and correlations between structure and function indicate that the beta turn is important for PTB domain recognition. These results show that PTB domains are functionally distinct from SH2 domains. Whereas SH2 domain binding specificity derives from peptide sequences carboxyl-terminal to phosphotyrosine, the Shc PTB domain gains specificity by interacting with beta turn-forming sequences amino-terminal to phosphotyrosine.

• vanderGeer P, Pawson T
• The PTB domain: a new protein module implicated in signal transduction.
• Trends Biochem Sci. 1995; 20: 277-80

Src homology 2 (SH2) domains have been identified in a large number of proteins involved in signal transduction downstream of receptor tyrosine kinases. They allow cytoplasmic signalling proteins to bind specifically to other polypeptides that are phosphorylated on tyrosine in response to growth factor stimulation. A novel phosphotyrosine-binding (PTB) domain has been identified recently in the amino terminus of Shc, an adaptor molecule that appears to be involved in Ras activation PTB domains are longer than SH2 domains, and recognize phosphotyrosine in the context of amino-terminal residues, in contrast to SH2 domains, which recognize them in the context of carboxy-terminal residues.

• Xiao B et al.
• Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways.
• Nature. 1995; 376: 188-91

A broad range of organisms and tissues contain 14-3-3 proteins, which have been associated with many diverse functions including critical roles in signal transduction pathways, exocytosis and cell cycle regulation. We report here the crystal structure of the human T-cell 14-3-3 isoform (tau) dimer at 2.6 A resolution. Each monomer (Mr 28K) is composed of an unusual arrangement of nine antiparallel alpha-helices organized as two structural domains. The dimer creates a large, negatively charged channel approximately 35 A broad, 35 A wide and 20 A deep. Overall, invariant residues line the interior of this channel whereas the more variable residues are distributed on the outer surface. At the base of this channel is a 16-residue segment of 14-3-3 which has been implicated in the binding of 14-3-3 to protein kinase C.

• Xu RX, Word JM, Davis DG, Rink MJ, WillardDHJ r, GampeRTJ r
• Solution structure of the human pp60c-src SH2 domain complexed with a phosphorylated tyrosine pentapeptide.
• Biochemistry. 1995; 34: 2107-21

Human pp60c-src is a cellular nonreceptor tyrosine kinase that participates in cytosolic signal transduction and has been implicated in the development of malignant tumors in the human breast and colon. Signal transduction is mediated by highly specific interactions between the SH2 domain and receptor phosphorylated tyrosine binding motifs. To elucidate the molecular conformation and interactions in solution, a family of highly resolved nuclear magnetic resonance (NMR) structures was determined for the src SH2 domain complexed with a high-affinity phosphorylated pentapeptide, acetyl-p YEEIE-OH. The 23 structures, generated with a distance geometry (DG) and a dynamical simulated annealing (SA) procedure, satisfied 2072 experimental restraints derived from a variety of multifrequency/multidimensional and isotope-filtered NMR data. Superimposition of residues 143-245 upon the mean coordinate set yielded an atomic rmsd of 0.58 +/- 0.09 A for the N, C alpha, C' atoms and 1.04 +/- 0.08 for all the non-hydrogen atoms. Residues in the ordered secondary structure regions superimpose to 0.29 +/- 0.04 A for the N, C alpha, C' and 0.73 +/- 0.08 A for all the non-hydrogen atoms. The angular order parameter calculated for the phi, psi angles was > 0.9 for 81 of the 106 protein residues. The main protein conformational features are three antiparallel beta-strands that traverse a compact core with an alpha-helix on each side of the core near the N- and C-termini. The observed intermolecular nuclear Overhauser effects (NOE) from the pY, +1E, and +3I residues positioned the ligand in an extended conformation across the SH2 domain surface with the pY and +3I side chains inserted into the protein binding pockets. In general, the protein conformation is consistent with previously reported structures of different SH2 domain complexes determined by X-ray crystallography. However, inter- or intramolecular interactions involving the guanidinium side chains of the solvated R alpha A2 or the buried R beta B5 were not observed at pH = 5.5 or 7.0. If such interactions exist in solution, the absence of any confirming data probably arises from rapid exchange with solvent and/or undetermined dynamic components. Thus, the unrestrained R alpha A2 side chain did not show an amino-aromatic interaction or a hydrogen bond to the -1 carbonyl oxygen as observed in the crystal structures. This result is consistent with the solution structure of a different SH2 domain complex. A more detailed comparison between the crystal structure and the NMR-derived solution structures of the same src SH2 domain complex is presented.(ABSTRACT TRUNCATED AT 400 WORDS)

• Zhou MM et al.
• Structure and ligand recognition of the phosphotyrosine binding domain of Shc.
• Nature. 1995; 378: 584-92

The nuclear magnetic resonance structure of the phosphotyrosine binding (PTB) domain of Shc complexed to a phosphopeptide reveals an alternative means of recognizing tyrosine-phosphorylated proteins. Unlike in SH2 domains, the phosphopeptide forms an antiparallel beta-strand with a beta-sheet of the protein, interacts with a hydrophobic pocket through the (pY-5) residue, and adopts a beta-turn. The PTB domain is structurally similar to pleckstrin homology domains (a beta-sandwich capped by an alpha-helix) and binds to acidic phospholipids, suggesting a possible role in membrane localization.

• Zhou MM et al.
• Solution structure of the Shc SH2 domain complexed with a tyrosine-phosphorylated peptide from the T-cell receptor.
• Proc Natl Acad Sci U S A. 1995; 92: 7784-8

She is a widely expressed adapter protein that plays an important role in signaling via a variety of cell surface receptors and has been implicated in coupling the stimulation of growth factor, cytokine, and antigen receptors to the Ras signaling pathway. She interacts with several tyrosine-phosphorylated receptors through its C-terminal SH2 domain, and one of the mechanisms of T-cell receptor-mediated Ras activation involves the interaction of the Shc SH2 domain with the tyrosine-phosphorylated zeta chain of the T-cell receptor. Here we describe a high-resolution NMR structure of the Shc SH2 domain complexed to a phosphopeptide (GHDGLpYQGLSTATK) corresponding to a portion of the zeta chain of the T-cell receptor. Although the overall architecture of the protein is similar to other SH2 domains, distinct structural differences were observed in the smaller beta-sheet, BG loop, (pY + 3) phosphopeptide-binding site, and relative position of the bound phosphopeptide.

• Barford D, Flint AJ, Tonks NK
• Crystal structure of human protein tyrosine phosphatase 1B.
• Science. 1994; 263: 1397-404

Protein tyrosine phosphatases (PTPs) constitute a family of receptor-like and cytoplasmic signal transducing enzymes that catalyze the dephosphorylation of phosphotyrosine residues and are characterized by homologous catalytic domains. The crystal structure of a representative member of this family, the 37-kilodalton form (residues 1 to 321) of PTP1B, has been determined at 2.8 A resolution. The enzyme consists of a single domain with the catalytic site located at the base of a shallow cleft. The phosphate recognition site is created from a loop that is located at the amino-terminus of an alpha helix. This site is formed from an 11-residue sequence motif that is diagnostic of PTPs and the dual specificity phosphatases, and that contains the catalytically essential cysteine and arginine residues. The position of the invariant cysteine residue within the phosphate binding site is consistent with its role as a nucleophile in the catalytic reaction. The structure of PTP1B should serve as a model for other members of the PTP family and as a framework for understanding the mechanism of tyrosine dephosphorylation.

• Borchert TV, Mathieu M, Zeelen JP, Courtneidge SA, Wierenga RK
• The crystal structure of human CskSH3: structural diversity near the RT-Src and n-Src loop.
• FEBS Lett. 1994; 341: 79-85

SH3 domains are modules occurring in diverse proteins, ranging from cytoskeletal proteins to signaling proteins, such as tyrosine kinases. The crystal structure of the SH3 domain of Csk (c-Src specific tyrosine kinase) has been refined at a resolution of 2.5 A, with an R-factor of 22.4%. The structure is very similar to the FynSH3 crystal structure. When comparing CskSH3 and FynSH3 it is seen that the structural and charge differences of the RT-Src loop and the n-Src loop, near the conserved Trp47, correlate with different binding properties of these SH3 domains. The structure comparison suggests that those glycines and acid residues which are very well conserved in the SH3 sequences are important for the stability of the SH3 fold.

• Carr MD, Bauer CJ, Gradwell MJ, Feeney J
• Solution structure of a trefoil-motif-containing cell growth factor, porcine spasmolytic protein.
• Proc Natl Acad Sci U S A. 1994; 91: 2206-10

The porcine spasmolytic protein (pSP) is a 106-residue cell growth factor that typifies a family of eukaryotic proteins that contain at least one copy of an approximately 40-amino acid protein domain known as the trefoil motif. In fact, pSP contains two highly homologous trefoil domains. We have determined the complete three-dimensional solution structure of pSP by using a combination of two- and three-dimensional 1H NMR spectroscopy and distance geometry calculations. pSP is a relatively elongated molecule, consisting of two compact globular domains joined via a small interface. The protein's two trefoil domains adopt the same tertiary structure and contain a core C-terminal two-stranded antiparallel beta-sheet, preceded by a 6-residue helix that packs against the N-terminal beta-strand. The remainder of the protein backbone is taken up by two short loops that lie on either side of the beta-hairpin and are linked by an extended region that wraps around the C-terminal beta-strand. The topology of the protein backbone observed for the trefoil domains in pSP represents an unusual polypeptide fold. A striking feature of both trefoil domains is a surface patch formed from five conserved residues that have no obvious structural role. The two patches are located at the far ends of the protein molecule, and we propose that these residues form at least part of the receptor binding site, or sites, on pSP.

• Eck MJ, Atwell SK, Shoelson SE, Harrison SC
• Structure of the regulatory domains of the Src-family tyrosine kinase Lck.
• Nature. 1994; 368: 764-9

The kinase p56lck (Lck) is a T-lymphocyte-specific member of the Src family of non-receptor tyrosine kinases. Members of the Src family each contain unique amino-terminal regions, followed by Src-homology domains SH3 and SH2, and a tyrosine kinase domain. SH3 and SH2 domains mediate critical protein interactions in many signal-transducing pathways. They are small, independently folded modules of about 60 and 100 residues, respectively, and they are often but not always found together in the same molecule. Like all nine Src-family kinases (reviewed in ref. 3), Lck is regulated by phosphorylation of a tyrosine in the short C-terminal tail of its catalytic domain. There is evidence that binding of the phosphorylated tail to the SH2 domain inhibits catalytic activity of the kinase domain and that the SH3 and SH2 domains may act together to effect this regulation. Here we report the crystal structures for a fragment of Lck bearing its SH3 and SH2 domains, alone and in complex with a phosphotyrosyl peptide containing the sequence of the Lck C-terminal regulatory tail. The latter complex represents the regulatory apparatus of Lck. The SH3-SH2 fragment forms similar dimers in both crystals, and the tail peptide binds at the intermolecular SH3/SH2 contact. The two structures show how an SH3 domain might recognize a specific target and suggest how dimerization could play a role in regulating Src-family kinases.

• Feng S, Chen JK, Yu H, Simon JA, Schreiber SL
• Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions.
• Science. 1994; 266: 1241-7

Solution structures of two Src homology 3 (SH3) domain-ligand complexes have been determined by nuclear magnetic resonance. Each complex consists of the SH3 domain and a nine-residue proline-rich peptide selected from a large library of ligands prepared by combinatorial synthesis. The bound ligands adopt a left-handed polyproline type II (PPII) helix, although the amino to carboxyl directionalities of their helices are opposite. The peptide orientation is determined by a salt bridge formed by the terminal arginine residues of the ligands and the conserved aspartate-99 of the SH3 domain. Residues at positions 3, 4, 6, and 7 of both peptides also intercalate into the ligand-binding site; however, the respective proline and nonproline residues show exchanged binding positions in the two complexes. These structural results led to a model for the interactions of SH3 domains with proline-rich peptides that can be used to predict critical residues in complexes of unknown structure. The model was used to identify correctly both the binding orientation and the contact and noncontact residues of a peptide derived from the nucleotide exchange factor Sos in association with the amino-terminal SH3 domain of the adaptor protein Grb2.

• Kavanaugh WM, Williams LT
• An alternative to SH2 domains for binding tyrosine-phosphorylated proteins.
• Science. 1994; 266: 1862-5

Src homology 2 (SH2) domains bind specifically to tyrosine-phosphorylated proteins that participate in signaling by growth factors and oncogenes. A protein domain was identified that bound specifically to the tyrosine-phosphorylated form of its target protein but differs from known SH2 sequences. Phosphotyrosine-binding (PTB) domains were found in two proteins: SHC, a protein implicated in signaling through Ras; and SCK, encoded by a previously uncharacterized gene. The PTB domain of SHC specifically bound to a tyrosine-phosphorylated 145-kilodalton protein. PTB domains are an alternative to SH2 domains for specifically recruiting tyrosine-phosphorylated proteins into signaling complexes and are likely to take part in signaling by many growth factors.

• Lee CH et al.
• Crystal structures of peptide complexes of the amino-terminal SH2 domain of the Syp tyrosine phosphatase.
• Structure. 1994; 2: 423-38

BACKGROUND: Src homology 2 (SH2) domains bind to phosphotyrosine residues in a sequence-specific manner, and thereby couple tyrosine phosphorylation to changes in the localization or catalytic activity of signal transducing molecules. Current understanding of SH2 specificity is based on the structures of SH2-peptide complexes of the closely-related Src and Lck tyrosine kinases. The tyrosine phosphatase Syp contains two SH2 domains that are relatively divergent from those of the tyrosine kinases, with distinct target specificities, and is thus well suited for structural studies aimed at extending our understanding of SH2 specificity. RESULTS: Crystal structures of the amino-terminal SH2 domain of Syp in separate complexes with two high-affinity peptides, in complex with a non-specific peptide and in the uncomplexed form have been determined at between 2 A and 3 A resolution. The structure of the SH2 domain and the mode of high-affinity peptide binding is essentially similar to that seen in the Src and Lck structures. However, the binding interface is more extensive in Syp. CONCLUSIONS: Most SH2 targets have hydrophobic residues at the third position following the phosphotyrosine, and the Syp structure confirms that the peptide is anchored to the SH2 surface by this residue and by the phosphotyrosine. In addition, the Syp structure has revealed that sequence specificity can extend across the five residues following the phosphotyrosine, and has shown how the SH2 domain's surface topography can be altered with resulting changes in specificity, while conserving the structure of the central core of the domain.

• Lim WA, Richards FM, Fox RO
• Structural determinants of peptide-binding orientation and of sequence specificity in SH3 domains.
• Nature. 1994; 372: 375-9

The Src-homology-3 (SH3) domains of the Caenorhabditis elegans protein SEM-5 and its human and Drosophila homologues, Grb2 and Drk (refs 1-4), bind proline-rich sequences found in the nucleotide-exchange factor Sos as part of their proposed function linking receptor tyrosine kinase activation to Ras activation. Here we report the crystal structure at 2.0 A resolution of the carboxy-terminal SH3 domain from SEM-5 complexed to the mSos-derived amino-acid sequence PPPVPPRRR. The peptide is found to bind in an orientation ('minus') that is precisely opposite to that observed previously ('plus' orientation) in other SH3-peptide complexes. This novel ability of peptide-recognition proteins to recognize peptides in two distinct modes may play an important role in the signalling specificity of pathways involving SH3 domains. Comparison of this structure with other SH3 complexes reveals how a conserved binding face can be used to recognize peptides in different orientations, and why the Sos peptide binds in this particular orientation.

• Musacchio A, Saraste M, Wilmanns M
• High-resolution crystal structures of tyrosine kinase SH3 domains complexed with proline-rich peptides.
• Nat Struct Biol. 1994; 1: 546-51

Src-homology 3 (SH3) domains bind to proline-rich motifs in target proteins. We have determined high-resolution crystal structures of the complexes between the SH3 domains of Abl and Fyn tyrosine kinases, and two ten-residue proline-rich peptides derived from the SH3-binding proteins 3BP-1 and 3BP-2. The X-ray data show that the basic mode of binding of both proline-rich peptides is the same. Peptides are bound over their entire length and interact with three major sites on the SH3 molecules by both hydrogen-bonding and van der Waals contacts. Residues 4-10 of the peptide adopt the conformation of a left-handed polyproline helix type II. Binding of the proline at position 2 requires a kink at the non-proline position 3.

• Pascal SM et al.
• Nuclear magnetic resonance structure of an SH2 domain of phospholipase C-gamma 1 complexed with a high affinity binding peptide.
• Cell. 1994; 77: 461-72

The solution structure of the C-terminal SH2 domain of phospholipase C-gamma 1 (PLC-gamma 1), in complex with a phosphopeptide corresponding to its Tyr-1021 high affinity binding site on the platelet-derived growth factor receptor, has been determined by nuclear magnetic resonance spectroscopy. The topology of the SH2-phosphopeptide complex is similar to previously reported Src and Lck SH2 complexes. However, the binding site for residues C-terminal to the phosphotyrosine (pTyr) is an extended groove that contacts peptide residues at the +1 to +6 positions relative to the pTyr. This striking difference from Src and Lck reflects the fact that the PLC-gamma 1 complex involves binding of a phosphopeptide with predominantly hydrophobic residues C-terminal to the pTyr and therefore serves as a prototype for a second class of SH2-phosphopeptide interactions.

• Wittekind M et al.
• Orientation of peptide fragments from Sos proteins bound to the N-terminal SH3 domain of Grb2 determined by NMR spectroscopy.
• Biochemistry. 1994; 33: 13531-9

NMR spectroscopy has been used to characterize the protein-protein interactions between the mouse Grb2 (mGrb2) N-terminal SH3 domain complexed with a 15-residue peptide (SPLLPKLPP-KTYKRE) corresponding to residues 1264-1278 of the mouse Sos-2 (mSos-2) protein. Intermolecular interactions between the peptide and 13C-15N-labeled SH3 domain were identified in half-reverse-filtered 2D and 3D NOESY experiments. Assignments for the protons involved in interactions between the peptide and the SH3 domain were confirmed in a series of NOESY experiments using a set of peptides in which different leucine positions were fully deuterated. The peptide ligand-binding site of the mGrb2 N-terminal SH3 domain is defined by the side chains of specific aromatic residues (Tyr7, Phe9, Trp36, Tyr52) that form two hydrophobic subsites contacting the side chains of the peptide Leu4 and Leu7 residues. An adjacent negatively charged subsite on the SH3 surface is likely to interact with the side chain of a basic residue at peptide position 10 that we show to be involved in binding. The peptide-binding site of the SH3 is characterized by large perturbations of amide chemical shifts when the peptide is added to the SH3 domain. The mGrb2 N-terminal SH3 domain structure in the complex is well-defined (backbone RMSD of 0.56 +/- 0.21 calculated over the backbone N, C alpha, and C atoms of residues 1-54). The structure of the peptide in the complex is less well-defined but displays a distinct orientation.(ABSTRACT TRUNCATED AT 250 WORDS)

• Yoon HS, Hajduk PJ, Petros AM, Olejniczak ET, Meadows RP, Fesik SW
• Solution structure of a pleckstrin-homology domain.
• Nature. 1994; 369: 672-5

Pleckstrin, the major protein kinase C substrate of platelets, contains domains of about 100 amino acids at the amino and carboxy termini that have been found in a number of proteins, including serine/threonine kinases, GTPase-activating proteins, phospholipases and cytoskeletal proteins. These conserved sequences, termed pleckstrin-homology (PH) domains, are thought to be involved in signal transduction. But the details of the function and binding partners of the PH domains have not been characterized. Here we report the solution structure of the N-terminal pleckstrin-homology domain of pleckstrin determined using heteronuclear three-dimensional nuclear magnetic resonance spectroscopy. The structure consists of an up-and-down beta-barrel of seven antiparallel beta-strands and a C-terminal amphiphilic alpha-helix that caps one end of the barrel. The overall topology of the domain is similar to that of the retinol-binding protein family of structures.

• Booker GW et al.
• Solution structure and ligand-binding site of the SH3 domain of the p85 alpha subunit of phosphatidylinositol 3-kinase.
• Cell. 1993; 73: 813-22

SH3 domains are found in proteins associated with receptor tyrosine kinase signal transduction complexes. The solution structure of the SH3 domain of the 85 kd regulatory subunit of phosphatidylinositol 3-kinase is shown to be a compact beta barrel consisting of five beta strands arranged in two beta sheets of three and two strands. The structure is similar to that of chicken brain alpha spectrin but represents a distinct class of SH3 domain, with an insertion between the second and third beta strands that may influence binding specificity. 1H chemical shift changes induced by complex formation with a synthetic peptide derived from the SH3-binding protein dynamin, together with amino acid sequence comparisons, suggest that the ligand-binding site consists of a hydrophobic surface flanked by two charged loops.

• Eck MJ, Shoelson SE, Harrison SC
• Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck.
• Nature. 1993; 362: 87-91

The Src homology-2 (SH2) domains are modules of about 100 amino-acid residues that are found in many intracellular signal-transduction proteins. They bind phosphotyrosine-containing sequences with high affinity and specificity, recognizing phosphotyrosine in the context of the immediately adjacent polypeptide sequence. The protein p56lck (Lck) is a Src-like, lymphocyte-specific tyrosine kinase. A phosphopeptide library screen has recently been used to deduce an 'optimal' binding sequence for the Lck SH2 domain. There is selectivity for the residues Glu, Glu and Ile in the three positions C-terminal to the phosphotyrosine. An 11-residue phosphopeptide derived from the hamster polyoma middle-T antigen, EPQpYEEIPIYL, binds with an approximately 1 nM dissociation constant to the Lck SH2 (ref. 17), an affinity equivalent to that of the tightest known SH2-phosphopeptide complex. We report here the high-resolution crystallographic analysis of the Lck SH2 domain in complex with this phosphopeptide. Recent crystallographically derived structures of the Src SH2 domain in complex with low-affinity peptides, which do not contain the EEI consensus, and NMR-derived structures of unliganded Abl (ref. 19) and p85 (ref. 20) SH2 domains have revealed the conserved fold of the SH2 domain and the properties of a phosphotyrosine binding pocket. Our high-affinity complex shows the presence of a second pocket for the residue (pY + 3) three positions C-terminal to the phosphotyrosine (pY). The peptide is anchored by insertion of the pY and pY + 3 side chains into their pockets and by a network of hydrogen bonds to the peptide main chain. In the low-affinity phosphopeptide/Src complexes, the pY + 3 residues do not insert into the homologous binding pocket and the peptide main chain remains displaced from the surface of the domain.

• Kohda D et al.
• Solution structure of the SH3 domain of phospholipase C-gamma.
• Cell. 1993; 72: 953-60

SH3 (Src homology 3) domains are found in many signaling proteins and appear to function as binding modules for cytoplasmic target proteins. The solution structure of the SH3 domain of human phospholipase C-gamma (PLC-gamma) was determined by two-dimensional 1H NMR analysis. This SH3 domain is composed of eight antiparallel beta strands consisting of two successive "Greek key" motifs, which form a barrel-like structure. The conserved aliphatic and aromatic residues form a hydrophobic pocket on the molecular surface, and the conserved carboxylic residues are localized to the periphery. The hydrophobic pocket may serve as a binding site for target proteins. Analysis of the slowly exchanging amide protons by NMR measurements indicates that despite containing a high content of beta structure, the SH3 domain of PLC-gamma is flexible.

• Koyama S, Yu H, Dalgarno DC, Shin TB, Zydowsky LD, Schreiber SL
• Structure of the PI3K SH3 domain and analysis of the SH3 family.
• Cell. 1993; 72: 945-52

Src homology 3 (SH3) domains, which are found in many proteins involved in intracellular signal transduction, mediate specific protein-protein interactions. The three-dimensional structure of the SH3 domain in the p85 subunit of the phosphatidylinositol 3-kinase (PI3K) has been determined by multidimensional NMR methods. The molecule consists of four short helices, two beta turns, and two antiparallel beta sheets. The beta sheets are highly similar to corresponding regions in the SH3 domain of the tyrosine kinase Src, even though the sequence identity of the two domains is low. There is a unique 15 amino acid insert in PI3K that contains three short helices. There are substantial differences in the identity of the amino acids that make up the receptor site of SH3 domains. The results suggest that while the overall structures of the binding sites in the PI3K and Src SH3 domains are similar, their ligand binding properties may differ.

• Maclennan AJ, Shaw G
• A yeast SH2 domain.
• Trends Biochem Sci. 1993; 18: 464-5

• Noble ME, Musacchio A, Saraste M, Courtneidge SA, Wierenga RK
• Crystal structure of the SH3 domain in human Fyn; comparison of the three-dimensional structures of SH3 domains in tyrosine kinases and spectrin.
• EMBO J. 1993; 12: 2617-24

The Src-homology 3 (SH3) region is a protein domain consisting of approximately 60 residues. It occurs in a large number of eukaryotic proteins involved in signal transduction, cell polarization and membrane--cytoskeleton interactions. The function is unknown, but it is probably involved in specific protein--protein interactions. Here we report the crystal structure of the SH3 domain of Fyn (a Src family tyrosine kinase) at 1.9 A resolution. The crystals have two SH3 molecules per asymmetric unit. These two Fyn SH3 domains are not related by a local twofold axis. The crystal structures of spectrin and Fyn SH3 domains as well as the solution structure of the Src SH3 domain show that these all have the same basic fold. A protein domain which has the same topology as SH3 is present in the prokaryotic regulatory enzyme BirA. The comparison between the crystal structures of Fyn and spectrin SH3 domains shows that a conserved surface patch, consisting mainly of aromatic residues, is flanked by two hairpin-like loops (residues 94-104 and 114-118 in Fyn). These loops are different in tyrosine kinase and spectrin SH3 domains. They could modulate the binding properties of the aromatic surface.

• Waksman G, Shoelson SE, Pant N, Cowburn D, Kuriyan J
• Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms.
• Cell. 1993; 72: 779-90

The crystal structure of the Src SH2 domain complexed with a high affinity 11-residue phosphopeptide has been determined at 2.7 A resolution by X-ray diffraction. The peptide binds in an extended conformation and makes primary interactions with the SH2 domain at six central residues: PQ(pY)EEI. The phosphotyrosine and the isoleucine are tightly bound by two well-defined pockets on the protein surface, resulting in a complex that resembles a two-pronged plug engaging a two-holed socket. The glutamate residues are in solvent-exposed environments in the vicinity of basic side chains of the SH2 domain, and the two N-terminal residues cap the phosphotyrosine-binding site. The crystal structure of Src SH2 in the absence of peptide has been determined at 2.5 A resolution, and comparison with the structure of the high affinity complex reveals only localized and relatively small changes.

• Booker GW et al.
• Structure of an SH2 domain of the p85 alpha subunit of phosphatidylinositol-3-OH kinase.
• Nature. 1992; 358: 684-7

Receptor protein-tyrosine kinases, through phosphorylation of specific tyrosine residues, generate high-affinity binding sites which direct assembly of multienzyme signalling complexes. Many of these signalling proteins, including phospholipase C gamma, GTPase-activating protein and phosphatidylinositol-3-OH kinase, contain src-homology 2 (SH2) domains, which bind with high affinity and specificity to tyrosine-phosphorylated sequences. The critical role played by SH2 domains in signalling has been highlighted by recent studies showing that mutation of specific phosphorylation sites on the platelet-derived growth factor receptor impair its association with phosphatidylinositol-3-OH kinase, preventing growth factor-induced mitogenesis. Here we report the solution structure of an isolated SH2 domain from the 85K regulatory subunit of phosphatidylinositol-3-OH kinase, determined using multidimensional nuclear magnetic resonance spectroscopy. The structure is characterized by a central region of beta-sheet flanked by two alpha-helices, with a highly flexible loop close to functionally important residues previously identified by site-directed mutagenesis.

• Musacchio A, Noble M, Pauptit R, Wierenga R, Saraste M
• Crystal structure of a Src-homology 3 (SH3) domain.
• Nature. 1992; 359: 851-5

The Src-homologous SH3 domain is a small domain present in a large number of proteins that are involved in signal transduction, such as the Src protein tyrosine kinase, or in membrane-cytoskeleton interactions, but the function of SH3 is still unknown (reviewed in refs 1-3). Here we report the three-dimensional structure at 1.8 A resolution of the SH3 domain of the cytoskeletal protein spectrin expressed in Escherichia coli. The domain is a compact beta-barrel made of five antiparallel beta-strands. The amino acids that are conserved in the SH3 sequences are located close to each other on one side of the molecule. This surface is rich in aromatic and carboxylic amino acids, and is distal to the region of the molecule where the N and C termini reside and where SH3 inserts into the alpha-spectrin chain. We suggest that a protein ligand binds to this conserved surface of SH3.

• Overduin M, Rios CB, Mayer BJ, Baltimore D, Cowburn D
• Three-dimensional solution structure of the src homology 2 domain of c-abl.
• Cell. 1992; 70: 697-704

SH2 regions are protein motifs capable of binding target protein sequences that contain a phosphotyrosine. The solution structure of the abl SH2 product, a protein of 109 residues and 12.1 kd, has been determined by multidimensional nuclear magnetic resonance spectroscopy. It is a compact spherical domain with a pair of three-stranded antiparallel beta sheets and a C-terminal alpha helix enclosing the hydrophobic core. Three arginines project from a short N-terminal alpha helix and one beta sheet into the putative phosphotyrosine-binding site, which lies on a face distal from the termini. Comparison with other SH2 sequences supports a common global fold and mode of phosphotyrosine binding for this family.

• Waksman G et al.
• Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides.
• Nature. 1992; 358: 646-53

Three-dimensional structures of complexes of the SH2 domain of the v-src oncogene product with two phosphotyrosyl peptides have been determined by X-ray crystallography at resolutions of 1.5 and 2.0 A, respectively. A central antiparallel beta-sheet in the structure is flanked by two alpha-helices, with peptide binding mediated by the sheet, intervening loops and one of the helices. The specific recognition of phosphotyrosine involves amino-aromatic interactions between lysine and arginine side chains and the ring system in addition to hydrogen-bonding interactions with the phosphate.

• Yu H, Rosen MK, Shin TB, Seidel-Dugan C, Brugge JS, Schreiber SL
• Solution structure of the SH3 domain of Src and identification of its ligand-binding site.
• Science. 1992; 258: 1665-8

The Src homology 3 (SH3) region is a protein domain of 55 to 75 amino acids found in many cytoplasmic proteins, including those that participate in signal transduction pathways. The solution structure of the SH3 domain of the tyrosine kinase Src was determined by multidimensional nuclear magnetic resonance methods. The molecule is composed of two short three-stranded anti-parallel beta sheets packed together at approximately right angles. Studies of the SH3 domain bound to proline-rich peptide ligands revealed a hydrophobic binding site on the surface of the protein that is lined with the side chains of conserved aromatic amino acids.

• Mayer BJ, Hamaguchi M, Hanafusa H
• A novel viral oncogene with structural similarity to phospholipase C.
• Nature. 1988; 332: 272-5

Numerous oncogenes have been isolated from acutely transforming retroviruses. To date, the products of these viral oncogenes have been protein kinases, nuclear proteins, growth factors, or GTP-binding proteins. We have cloned the previously uncharacterized avian sarcoma virus CT10 and sequenced its genome. This virus encodes a protein, p47gag-crk, that has blocks of sequence similarity to the amino-terminal, non-catalytic region of the non-receptor class of tyrosine kinases. In addition, the structure of p47gag-crk has striking similarity to a 180-amino acid region of bovine brain phospholipase C. Biochemical data suggest that p47gag-crk activates one or several endogenous tyrosine kinases.

• Stahl ML, Ferenz CR, Kelleher KL, Kriz RW, Knopf JL
• Sequence similarity of phospholipase C with the non-catalytic region of src.
• Nature. 1988; 332: 269-72

The production of the second messenger molecules diacylglycerol and inositol 1,4,5-trisphosphate is mediated by activated phosphatidylinositol-specific phospholipase C (PLC) enzymes. Here we report the cloning of a bovine brain complementary DNA encoding an enzyme PLC-148 that is characterized by calcium-dependent and phosphatidylinositol-specific phospholipase C activity when expressed in mammalian cells. Bovine brain messenger RNA contains a 7.5-kilobase transcript corresponding to the isolated cDNA; a related transcript of the same size is present in mRNA from some but not all human cell lines tested. Southern blot analysis of the bovine genome indicated that one or possibly two genes hybridize to the cloned PLC-148 cDNA. There is a striking sequence similarity between specific regions of PLC-148 and the non-catalytic domain of the non-receptor tyrosine kinases. The newly characterized crk transforming gene of the avian sarcoma virus CT10 also contains extensive sequence similarities with PLC-148.

• Sadowski I, Stone JC, Pawson T
• A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps.
• Mol Cell Biol. 1986; 6: 4396-408

Proteins encoded by oncogenes such as v-fps/fes, v-src, v-yes, v-abl, and v-fgr are cytoplasmic protein tyrosine kinases which, unlike transmembrane receptors, are localized to the inside of the cell. These proteins possess two contiguous regions of sequence identity: a C-terminal catalytic domain of 260 residues with homology to other tyrosine-specific and serine-threonine-specific protein kinases, and a unique domain of approximately 100 residues which is located N terminal to the kinase region and is absent from kinases that span the plasma membrane. In-frame linker insertion mutations in Fujinami avian sarcoma virus which introduced dipeptide insertions into the most stringently conserved segment of this N-terminal domain in P130gag-fps impaired the ability of Fujinami avian sarcoma virus to transform rat-2 cells. The P130gag-fps proteins encoded by these transformation-defective mutants were deficient in protein-tyrosine kinase activity in rat cells. However v-fps polypeptides derived from the mutant Fujinami avian sarcoma virus genomes and expressed in Escherichia coli as trpE-v-fps fusion proteins displayed essentially wild-type enzymatic activity, even though they contained the mutated sites. Deletion of the N-terminal domain from wild-type and mutant v-fps bacterial proteins had little effect on autophosphorylating activity. The conserved N-terminal domain of P130gag-fps is therefore not required for catalytic activity, but can profoundly influence the adjacent kinase region. The presence of this noncatalytic domain in all known cytoplasmic tyrosine kinases of higher and lower eucaryotes argues for an important biological function. The relative inactivity of the mutant proteins in rat-2 cells compared with bacteria suggests that the noncatalytic domain may direct specific interactions of the enzymatic region with cellular components that regulate or mediate tyrosine kinase function.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the SH2 domain.

Protein	Disease
Ras GTPase-activating protein 1 (P20936) (SMART)	OMIM:139150: Basal cell carcinoma
Tyrosine-protein kinase BTK (Q06187) (SMART)	OMIM:300300: Agammaglobulinemia, type 1, X-linked ; ?XLA and isolated growth hormone deficiency OMIM:307200:
SH2 domain-containing protein 1A (O60880) (SMART)	OMIM:308240: Lymphoproliferative syndrome, X-linked

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
7.91	map04630	Jak-STAT signaling pathway
7.06	map04650	Natural killer cell mediated cytotoxicity
5.91	map04012	ErbB signaling pathway
5.91	map04660	T cell receptor signaling pathway
5.42	map04910	Insulin signaling pathway
4.89	map04664	Fc epsilon RI signaling pathway
4.58	map04510	Focal adhesion
4.22	map05220	Chronic myeloid leukemia
3.82	map04662	B cell receptor signaling pathway
3.47	map04670	Leukocyte transendothelial migration
3.07	map05214	Glioma
2.84	map04810	Regulation of actin cytoskeleton
2.44	map05211	Renal cell carcinoma
2.40	map04930	Type II diabetes mellitus
2.31	map05120	Epithelial cell signaling in Helicobacter pylori infection
2.18	map04370	VEGF signaling pathway
2.18	map04070	Phosphatidylinositol signaling system
2.09	map05223	Non-small cell lung cancer
2.04	map04360	Axon guidance
2.00	map04920	Adipocytokine signaling pathway
1.60	map04520	Adherens junction
1.51	map04010	MAPK signaling pathway
1.42	map05213	Endometrial cancer
1.42	map05210	Colorectal cancer
1.42	map05215	Prostate cancer
1.42	map05221	Acute myeloid leukemia
1.20	map04120	Ubiquitin mediated proteolysis
1.02	map00562	Inositol phosphate metabolism
0.98	map05222	Small cell lung cancer
0.98	map05212	Pancreatic cancer
0.98	map04620	Toll-like receptor signaling pathway
0.98	map04210	Apoptosis
0.98	map04150	mTOR signaling pathway
0.98	map05218	Melanoma
0.98	map04914	Progesterone-mediated oocyte maturation
0.84	map04530	Tight junction
0.84	map04912	GnRH signaling pathway
0.84	map04540	Gap junction
0.84	map05040	Huntington's disease
0.67	map04020	Calcium signaling pathway
0.44	map04320	Dorso-ventral axis formation
0.44	map04730	Long-term depression
0.36	map04110	Cell cycle
0.04	map00970	Aminoacyl-tRNA biosynthesis
0.04	map00251	Glutamate metabolism
0.04	map00860	Porphyrin and chlorophyll metabolism

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with SH2 domain which could be assigned to a KEGG orthologous group, and not all proteins containing SH2 domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of SH2 domains in PDB

PDB code	Title
1a07	C-SRC (SH2 DOMAIN) COMPLEXED WITH ACE-MALONYL TYR-GLU-(N,N-DIPENTYL AMINE)
1a08	C-SRC (SH2 DOMAIN) COMPLEXED WITH ACE-DIFLUORO PHOSPHOTYR-GLU-(N,N-DIPENTYL AMINE)
1a09	C-SRC (SH2 DOMAIN) COMPLEXED WITH ACE-FORMYL PHOSPHOTYR-GLU-(N,N-DIPENTYL AMINE)
1a1a	C-SRC (SH2 DOMAIN WITH C188A MUTATION) COMPLEXED WITH ACE-FORMYL PHOSPHOTYR-GLU-(N,N-DIPENTYL AMINE)
1a1b	C-SRC (SH2 DOMAIN) COMPLEXED WITH ACE-PHOSPHOTYR-GLU-(N,N-DIPENTYL AMINE)
1a1c	C-SRC (SH2 DOMAIN) COMPLEXED WITH ACE-PHOSPHOTYR-GLU-(N-ME(-(CH2)3-CYCLOPENTYL))
1a1e	C-SRC (SH2 DOMAIN) COMPLEXED WITH ACE-PHOSPHOTYR-GLU-(3-BUTYLPIPERIDINE)
1a81	CRYSTAL STRUCTURE OF THE TANDEM SH2 DOMAIN OF THE SYK KINASE BOUND TO A DUALLY TYROSINE-PHOSPHORYLATED ITAM
1ab2	THREE-DIMENSIONAL SOLUTION STRUCTURE OF THE SRC HOMOLOGY 2 DOMAIN OF C-ABL
1ad5	SRC FAMILY KINASE HCK-AMP-PNP COMPLEX
1aot	NMR STRUCTURE OF THE FYN SH2 DOMAIN COMPLEXED WITH A PHOSPHOTYROSYL PEPTIDE, MINIMIZED AVERAGE STRUCTURE
1aou	NMR STRUCTURE OF THE FYN SH2 DOMAIN COMPLEXED WITH A PHOSPHOTYROSYL PEPTIDE, 22 STRUCTURES
1aya	CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE
1ayb	CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE
1ayc	CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE
1ayd	CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE
1bf5	TYROSINE PHOSPHORYLATED STAT-1/DNA COMPLEX
1bfi	SOLUTION STRUCTURE OF THE C-TERMINAL SH2 DOMAIN OF THE P85ALPHA REGULATORY SUBUNIT OF PHOSPHOINOSITIDE 3-KINASE, NMR, 30 STRUCTURES
1bfj	SOLUTION STRUCTURE OF THE C-TERMINAL SH2 DOMAIN OF THE P85ALPHA REGULATORY SUBUNIT OF PHOSPHOINOSITIDE 3-KINASE, NMR, MINIMIZED AVERAGE STRUCTURE
1bg1	TRANSCRIPTION FACTOR STAT3B/DNA COMPLEX
1bhf	P56LCK SH2 DOMAIN INHIBITOR COMPLEX
1bhh	FREE P56LCK SH2 DOMAIN
1bkl	SELF-ASSOCIATED APO SRC SH2 DOMAIN
1bkm	COCRYSTAL STRUCTURE OF D-AMINO ACID SUBSTITUTED PHOSPHOPEPTIDE COMPLEX
1blj	NMR ENSEMBLE OF BLK SH2 DOMAIN, 20 STRUCTURES
1blk	NMR ENSEMBLE OF BLK SH2 DOMAIN USING CHEMICAL SHIFT REFINEMENT, 20 STRUCTURES
1bm2	GRB2-SH2 DOMAIN IN COMPLEX WITH CYCLO-[N-ALPHA-ACETYL-L-THI ALYSYL-O-PHOSPHOTYROSYL-VALYL-ASPARAGYL-VALYL-PROLYL] (PKF273-791)
1bmb	GRB2-SH2 DOMAIN IN COMPLEX WITH KPFY*VNVEF (PKF270-974)
1cj1	GROWTH FACTOR RECEPTOR BINDING PROTEIN SH2 DOMAIN (HUMAN) COMPLEXED WITH A PHOSPHOTYROSYL DERIVATIVE
1csy	SYK TYROSINE KINASE C-TERMINAL SH2 DOMAIN COMPLEXED WITH A PHOSPHOPEPTIDEFROM THE GAMMA CHAIN OF THE HIGH AFFINITY IMMUNOGLOBIN G RECEPTOR, NMR
1csz	SYK TYROSINE KINASE C-TERMINAL SH2 DOMAIN COMPLEXED WITH A PHOSPHOPEPTIDEFROM THE GAMMA CHAIN OF THE HIGH AFFINITY IMMUNOGLOBIN G RECEPTOR, NMR
1cwd	HUMAN P56LCK TYROSINE KINASE COMPLEXED WITH PHOSPHONOPEPTIDE
1cwe	HUMAN P56LCK TYROSINE KINASE COMPLEXED WITH PHOSPHONOPEPTIDE
1d1z	CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP
1d4t	CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP IN COMPLEX WITH A SLAM PEPTIDE
1d4w	CRYSTAL STRUCTURE OF THE XLP PROTEIN SAP IN COMPLEX WITH SLAM PHOSPHOPEPTIDE
1f1w	SRC SH2 THREF1TRP MUTANT COMPLEXED WITH THE PHOSPHOPEPTIDE S(PTR)VNVQN
1f2f	SRC SH2 THREF1TRP MUTANT
1fbz	Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity
1fhs	THE THREE-DIMENSIONAL SOLUTION STRUCTURE OF THE SRC HOMOLOGY DOMAIN-2 OF THE GROWTH FACTOR RECEPTOR BOUND PROTEIN-2, NMR, 18 STRUCTURES
1fmk	CRYSTAL STRUCTURE OF HUMAN TYROSINE-PROTEIN KINASE C-SRC
1fu5	NMR STRUCTURE OF THE N-SH2 DOMAIN OF THE P85 SUBUNIT OF PI3-KINASE COMPLEXED TO A DOUBLY PHOSPHORYLATED PEPTIDE DERIVED FROM POLYOMAVIRUS MIDDLE T ANTIGEN
1fu6	NMR STRUCTURE OF THE N-SH2 DOMAIN OF THE P85 SUBUNIT OF PI3-KINASE
1fyr	DIMER FORMATION THROUGH DOMAIN SWAPPING IN THE CRYSTAL STRUCTURE OF THE GRB2-SH2 AC-PYVNV COMPLEX
1g83	CRYSTAL STRUCTURE OF FYN SH3-SH2
1ghu	NMR SOLUTION STRUCTURE OF GROWTH FACTOR RECEPTOR-BOUND PROTEIN 2 (GRB2) SH2 DOMAIN, 24 STRUCTURES
1gri	GRB2
1h9o	PHOSPHATIDYLINOSITOL 3-KINASE, P85-ALPHA SUBUNIT: C-TERMINAL SH2 DOMAIN COMPLEXED WITH A TYR751 PHOSPHOPEPTIDE FROM THE PDGF RECEPTOR, CRYSTAL STRUCTURE AT 1.79 A
1hcs	NMR STRUCTURE OF THE HUMAN SRC SH2 DOMAIN COMPLEX
1hct	NMR STRUCTURE OF THE HUMAN SRC SH2 DOMAIN COMPLEX
1i3z	MURINE EAT2 SH2 DOMAIN IN COMPLEX WITH SLAM PHOSPHOPEPTIDE
1ijr	Crystal structure of LCK SH2 complexed with nonpeptide phosphotyrosine mimetic
1is0	Crystal Structure of a Complex of the Src SH2 Domain with Conformationally Constrained Peptide Inhibitor
1ju5	Ternary complex of an Crk SH2 domain, Crk-derived phophopeptide, and Abl SH3 domain by NMR spectroscopy
1jwo	Crystal Structure Analysis of the SH2 Domain of the Csk Homologous Kinase CHK
1jyq	Xray Structure of Grb2 SH2 Domain Complexed with a Highly Affine Phospho Peptide
1jyr	Xray Structure of Grb2 SH2 Domain Complexed with a Phosphorylated Peptide
1jyu	Xray Structure of Grb2 SH2 Domain
1k9a	Crystal structure analysis of full-length carboxyl-terminal Src kinase at 2.5 A resolution
1ka6	SAP/SH2D1A bound to peptide n-pY
1ka7	SAP/SH2D1A bound to peptide n-Y-c
1kc2	structure of the triple (Lys(beta)D3Ala, Asp(beta)C8Ala, AspCD2Ala) mutant of the Src SH2 domain bound to the PQpYEEIPI peptide
1ksw	Structure of Human c-Src Tyrosine Kinase (Thr338Gly Mutant) in Complex with N6-benzyl ADP
1lcj	SH2 (SRC HOMOLOGY-2) DOMAIN OF HUMAN P56-LCK TYROSINE KINASE COMPLEXED WITH THE 11 RESIDUE PHOSPHOTYROSYL PEPTIDE EPQPYEEIPIYL
1lck	SH3-SH2 DOMAIN FRAGMENT OF HUMAN P56-LCK TYROSINE KINASE COMPLEXED WITH THE 10 RESIDUE SYNTHETIC PHOSPHOTYROSYL PEPTIDE TEGQPYQPQPA
1lkk	HUMAN P56-LCK TYROSINE KINASE SH2 DOMAIN IN COMPLEX WITH THE PHOSPHOTYROSYL PEPTIDE AC-PTYR-GLU-GLU-ILE (PYEEI PEPTIDE)
1lkl	HUMAN P56-LCK TYROSINE KINASE SH2 DOMAIN IN COMPLEX WITH THE PHOSPHOTYROSYL PEPTIDE AC-PTYR-GLU-GLU-GLY (PYEEG PEPTIDE)
1lui	NMR Structures of Itk SH2 domain, Pro287cis isoform, ensemble of 20 low energy structures
1luk	NMR Structure of the Itk SH2 domain, Pro287cis, Energy minimized average structure
1lum	NMR Structure of the Itk SH2 domain, Pro287trans, 20 low energy structures
1lun	NMR Structure of the Itk SH2 domain, Pro287trans, energy minimized average structure
1m27	Crystal structure of SAP/FynSH3/SLAM ternary complex
1m61	Crystal structure of the apo SH2 domains of ZAP-70
1mil	TRANSFORMING PROTEIN
1mw4	Solution structure of the human Grb7-SH2 domain in complex with a 10 amino acid peptide pY1139
1nrv	Crystal structure of the SH2 domain of Grb10
1nzl	Crystal Structure of Src SH2 domain bound to doubly phosphorylated peptide PQpYEpYIPI
1nzv	Crystal Structure of Src SH2 domain bound to doubly phosphorylated peptide PQpYIpYVPA
1o41	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU78300.
1o42	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU81843.
1o43	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU82129.
1o44	Crystal structure of sh2 in complex with ru85052
1o45	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU84687.
1o46	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU90395.
1o47	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU82209.
1o48	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU85053.
1o49	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU85493.
1o4a	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU82197.
1o4b	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU83876.
1o4c	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH PHOSPHATE.
1o4d	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU78262.
1o4e	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU78299.
1o4f	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU79073.
1o4g	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH DPI59.
1o4h	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU79072.
1o4i	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH PAS219.
1o4j	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH ISO24.
1o4k	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH PASBN.
1o4l	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH FRAGMENT2.
1o4m	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH MALONICACID.
1o4n	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH OXALIC ACID.
1o4o	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH PHENYLPHOSPHATE.
1o4p	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU78791.
1o4q	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU79256.
1o4r	CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU78783.
1oo3	P395S mutant of the p85 regulatory subunit of the N-terminal src homology 2 domain of PI3-Kinase
1oo4	P395S mutant of the p85 regulatory subunit of the N-terminal src homology 2 domain of PI3-Kinase complexed to a peptide derived from PDGFr
1opk	Structural basis for the auto-inhibition of c-Abl tyrosine kinase
1opl	Structural basis for the auto-inhibition of c-Abl tyrosine kinase
1p13	Crystal Structure of the Src SH2 Domain Complexed with Peptide (SDpYANFK)
1pic	PHOSPHATIDYLINOSITOL 3-KINASE, P85-ALPHA SUBUNIT: C-TERMINAL SH2 DOMAIN COMPLEXED WITH A TYR751 PHOSPHOPEPTIDE FROM THE PDGF RECEPTOR, NMR, MINIMIZED MEAN STRUCTURE
1qad	Crystal Structure of the C-Terminal SH2 Domain of the P85 alpha Regulatory Subunit of Phosphoinositide 3-Kinase: An SH2 domain mimicking its own substrate
1qcf	CRYSTAL STRUCTURE OF HCK IN COMPLEX WITH A SRC FAMILY-SELECTIVE TYROSINE KINASE INHIBITOR
1qg1	GROWTH FACTOR RECEPTOR BINDING PROTEIN SH2 DOMAIN COMPLEXED WITH AN SHC-DERIVED PEPTIDE
1r1p	Structural Basis for Differential Recognition of Tyrosine Phosphorylated Sites in the Linker for Activation of T cells (LAT) by the Adaptor Protein Gads
1r1q	Structural Basis for Differential Recognition of Tyrosine Phosphorylated Sites in the Linker for Activation of T cells (LAT) by the Adaptor Protein Gads
1r1s	Structural Basis for Differential Recognition of Tyrosine Phosphorylated Sites in the Linker for Activation of T cells (LAT) by the Adaptor Protein Gads
1rja	Solution Structure and Backbone Dynamics of the Nonreceptor Tyrosine Kinase PTK6/Brk SH2 Domain
1rpy	CRYSTAL STRUCTURE OF THE DIMERIC SH2 DOMAIN OF APS
1rqq	Crystal Structure of the Insulin Receptor Kinase in Complex with the SH2 Domain of APS
1sha	CRYSTAL STRUCTURE OF THE PHOSPHOTYROSINE RECOGNITION DOMAIN SH2 OF V-SRC COMPLEXED WITH TYROSINE-PHOSPHORYLATED PEPTIDES
1shb	CRYSTAL STRUCTURE OF THE PHOSPHOTYROSINE RECOGNITION DOMAIN SH2 OF V-SRC COMPLEXED WITH TYROSINE-PHOSPHORYLATED PEPTIDES
1shd	PEPTIDE INHIBITORS OF SRC SH3-SH2-PHOSPHOPROTEIN INTERACTIONS
1skj	COCRYSTAL STRUCTURE OF UREA-SUBSTITUTED PHOSPHOPEPTIDE COMPLEX
1spr	BINDING OF A HIGH AFFINITY PHOSPHOTYROSYL PEPTIDE TO THE SRC SH2 DOMAIN: CRYSTAL STRUCTURES OF THE COMPLEXED AND PEPTIDE-FREE FORMS
1sps	BINDING OF A HIGH AFFINITY PHOSPHOTYROSYL PEPTIDE TO THE SRC SH2 DOMAIN: CRYSTAL STRUCTURES OF THE COMPLEXED AND PEPTIDE-FREE FORMS
1tce	SOLUTION NMR STRUCTURE OF THE SHC SH2 DOMAIN COMPLEXED WITH A TYROSINE-PHOSPHORYLATED PEPTIDE FROM THE T-CELL RECEPTOR, MINIMIZED AVERAGE STRUCTURE
1tze	SIGNAL TRANSDUCTION ADAPTOR GROWTH FACTOR, GRB2 SH2 DOMAIN COMPLEXED WITH PHOSPHOTYROSYL HEPTAPEPTIDE LYS-PRO-PHE-PTYR-VAL-ASN-VAL-NH2 (KFPPYVNC-NH2)
1uur	Structure of an activated Dictyostelium STAT in its DNA-unbound form
1uus	Structure of an activated Dictyostelium STAT in its DNA-unbound form
1wqu	Solution structure of the human FES SH2 domain
1x0n	NMR structure of growth factor receptor binding protein SH2 domain complexed with the inhibitor
1x27	Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas
1x6c	Solution structures of the SH2 domain of human protein-tyrosine phosphatase SHP-1
1xa6	Crystal Structure of the Human Beta2-Chimaerin
1y1u	Structure of unphosphorylated STAT5a
1y57	Structure of unphosphorylated c-Src in complex with an inhibitor
1yvl	Structure of Unphosphorylated STAT1
1z3k	Structural Insight into the Binding Diversity between the Tyr-Phosphorylated Human EphrinBs and Nck2 SH2 Domain
1zfp	GROWTH FACTOR RECEPTOR BINDING PROTEIN SH2 DOMAIN COMPLEXED WITH A PHOSPHOTYROSYL PENTAPEPTIDE
2abl	SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE
2aoa	Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
2aob	Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
2aug	Crystal structure of the Grb14 SH2 domain
2b3o	Crystal structure of human tyrosine phosphatase SHP-1
2bbu	solution structure of mouse socs3 in complex with a phosphopeptide from the gp130 receptor
2c0i	Src family kinase Hck with bound inhibitor A-420983
2c0o	Src family kinase Hck with bound inhibitor A-770041
2c0t	Src family kinase Hck with bound inhibitor A-641359
2c9w	CRYSTAL STRUCTURE OF SOCS-2 IN COMPLEX WITH ELONGIN-B AND ELONGIN-C AT 1.9A RESOLUTION
2ci8	sh2 domain of human nck1 adaptor protein - uncomplexed
2ci9	Nck1 SH2-domain in complex with a dodecaphosphopeptide from EPEC protein Tir
2cia	human nck2 sh2-domain in complex with a decaphosphopeptide from translocated intimin receptor (tir) of epec
2cr4	Solution structure of the SH2 domain of human SH3BP2 protein
2crh	Solution structure of the SH2 domain of human proto-oncogene protein VAV1
2cs0	Solution structure of the SH2 domain of human HSH2D protein
2dcr	Fully automated solution structure determination of the Fes SH2 domain
2dly	Solution structure of the SH2 domain of murine Fyn-related kinase
2dlz	Solution structure of the SH2 domain of human protein vav-2
2dm0	Solution structure of the SH2 domain of human Tyrosine-protein kinase TXK
2dvj	phosphorylated Crk-II
2dx0	Crystal structure of the N-terminal SH2 domain of mouse phospholipase C-gamma 2
2ecd	Solution structure of the human ABL2 SH2 domain
2ekx	Solution structure of the human BMX SH2 domain
2el8	Solution structure of the human STAP2 SH2 domain
2eo3	Solution structure of the SH2 domain from human Crk-like protein
2eo6	Solution structure of the SH2 domain from mouse B-cell linker protein BLNK
2eob	Solution structure of the second SH2 domain from rat PLC gamma-2
2etz	The NMR minimized average structure of the Itk SH2 domain bound to a phosphopeptide
2eu0	The NMR ensemble structure of the Itk SH2 domain bound to a phosphopeptide
2eyv	SH2 domain of CT10-Regulated Kinase
2eyy	CT10-Regulated Kinase isoform I
2eyz	CT10-Regulated Kinase isoform II
2fci	Structural basis for the requirement of two phosphotyrosines in signaling mediated by Syk tyrosine kinase
2fo0	Organization of the SH3-SH2 Unit in Active and Inactive Forms of the c-Abl Tyrosine Kinase
2ge9	Solution Structures of the SH2 domain of Bruton's Tyrosine Kinase
2gsb	Solution structure of the second SH2 domain of human Ras GTPase-activating protein 1
2h46	Native domain-swapped dimer crystal structure of the Grb2 SH2 domain
2h5k	Crystal Structure of Complex Between the Domain-Swapped Dimeric Grb2 SH2 Domain and Shc-Derived Ligand, Ac-NH-pTyr-Val-Asn-NH2
2h8h	Src kinase in complex with a quinazoline inhibitor
2hck	SRC FAMILY KINASE HCK-QUERCETIN COMPLEX
2hdv	Crystal structure of the Src Homology-2 domain of the adapter protein SH2-B
2hdx	Crystal structure of the Src homology-2 domain of SH2-B in complex with Jak2 pTyr813 phosphopeptide
2hmh	Crystal structure of SOCS3 in complex with gp130(pTyr757) phosphopeptide.
2huw	X-ray crystal structure of the Grb2 SH2 domain complexed to a constrained and cyclopropane-derived ligand
2iug	Crystal structure of the PI3-kinase p85 N-terminal SH2 domain
2iuh	Crystal structure of the PI3-kinase p85 N-terminal SH2 domain in complex with c-Kit phosphotyrosyl peptide
2iui	Crystal structure of the PI3-kinase p85 N-terminal SH2 domain in complex with PDGFR phosphotyrosyl peptide
2izv	CRYSTAL STRUCTURE OF SOCS-4 IN COMPLEX WITH ELONGIN-B AND ELONGIN-C AT 2.55A RESOLUTION
2jyq	NMR structure of the apo v-Src SH2 domain
2k79	Solution Structure of the binary complex between the SH3 and SH2 domain of interleukin-2 tyrosine kinase
2k7a	Ensemble Structures of the binary complex between the SH3 and SH2 domain of interleukin-2 tyrosine kinase.
2kk6	Solution structure of sh2 domain of proto-oncogene tyrosine-protein kinase fer from homo sapiens, northeast structural genomics consortium (nesg) target hr3461d
2kno	NMR Solution Structure of SH2 Domain of the Human Tensin Like C1 Domain Containing Phosphatase (TENC1)
2l3t	Solution structure of tandem SH2 domain from Spt6
2l4k	Water refined solution structure of the human Grb7-SH2 domain in complex with the 10 amino acid peptide pY1139
2l6k	Solution Structure of a Nonphosphorylated Peptide Recognizing Domain
2lct	Solution structure of the Vav1 SH2 domain complexed with a Syk-derived doubly phosphorylated peptide
2lnw	Identification and structural basis for a novel interaction between Vav2 and Arap3
2lnx	Solution structure of Vav2 SH2 domain
2lqn	Solution structure of CRKL
2lqw	Solution structure of phosphorylated CRKL
2mc1	Solution structure of the Vav1 SH2 domain complexed with a Syk-derived singly phosphorylated peptide
2mk2	Solution NMR structure of N-terminal domain (SH2 domain) of human Inositol polyphosphate phosphatase-like protein 1 (INPPL1) (fragment 20-117), Northeast Structural Genomics Consortium Target HR9134A
2mqi	2MQI
2mrj	2MRJ
2mrk	2MRK
2oq1	Tandem SH2 domains of ZAP-70 with 19-mer zeta1 peptide
2ozo	Autoinhibited intact human ZAP-70
2pld	NUCLEAR MAGNETIC RESONANCE STRUCTURE OF AN SH2 DOMAIN OF PHOSPHOLIPASE C-GAMMA1 COMPLEXED WITH A HIGH AFFINITY BINDING PEPTIDE
2ple	NUCLEAR MAGNETIC RESONANCE STRUCTURE OF AN SH2 DOMAIN OF PHOSPHOLIPASE C-GAMMA1 COMPLEXED WITH A HIGH AFFINITY BINDING PEPTIDE
2pna	STRUCTURE OF AN SH2 DOMAIN OF THE P85 ALPHA SUBUNIT OF PHOSPHATIDYLINOSITOL-3-OH KINASE
2pnb	STRUCTURE OF AN SH2 DOMAIN OF THE P85 ALPHA SUBUNIT OF PHOSPHATIDYLINOSITOL-3-OH KINASE
2ptk	CHICKEN SRC TYROSINE KINASE
2qms	Crystal structure of a signaling molecule
2rd0	Structure of a human p110alpha/p85alpha complex
2rmx	Solution structure of the SHP-1 C-terminal SH2 domain complexed with a tyrosine-phosphorylated peptide from NKG2A
2ror	Solution structure of the VAV1 SH2 domain complexed with a tyrosine-phosphorylated peptide from SLP76
2rsy	Solution structure of the SH2 domain of Csk in complex with a phosphopeptide from Cbp
2rvf	2RVF
2shp	TYROSINE PHOSPHATASE SHP-2
2src	CRYSTAL STRUCTURE OF HUMAN TYROSINE-PROTEIN KINASE C-SRC, IN COMPLEX WITH AMP-PNP
2vif	Crystal structure of SOCS6 SH2 domain in complex with a c-KIT phosphopeptide
2xp1	Structure of the tandem SH2 domains from Antonospora locustae transcription elongation factor Spt6
2y3a	Crystal structure of p110beta in complex with icSH2 of p85beta and the drug GDC-0941
2ysx	Solution structure of the human SHIP SH2 domain
2yu7	Solution structure of the SHP-1 C-terminal SH2 domain complexed with a tyrosine-phosphorylated peptide from NKG2A
3bkb	Crystal structure of human Feline Sarcoma Viral Oncogene Homologue (v-FES)
3c7i	X-RAY crystal structure of the complex between the grb2-sh2 domain and a flexible ligand, FPTVN.
3cbl	Crystal structure of human feline sarcoma viral oncogene homologue (v-FES) in complex with staurosporine and a consensus peptide
3cd3	Crystal structure of phosphorylated human feline sarcoma viral oncogene homologue (v-FES) in complex with staurosporine and a consensus peptide
3cwg	Unphosphorylated mouse STAT3 core fragment
3cxl	Crystal structure of human chimerin 1 (CHN1)
3eac	Crystal structure of SH2 domain of Human Csk (carboxyl-terminal src kinase), Oxidized form.
3eaz	Crystal structure of SH2 domain of Human Csk (carboxyl-terminal src kinase), C122S mutant.
3gqi	Crystal Structure of activated receptor tyrosine kinase in complex with substrates
3gxw	Structure of the SH2 domain of the Candida glabrata transcription elongation factor Spt6, crystal form A
3gxx	Structure of the SH2 domain of the Candida glabrata transcription elongation factor Spt6, crystal form B
3hck	NMR ENSEMBLE OF THE UNCOMPLEXED HUMAN HCK SH2 DOMAIN, 20 STRUCTURES
3hhm	Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha and the drug wortmannin
3hiz	Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha
3imd	Crystal Structure of the Grb2 SH2 Domain in Complex with a Flexible Ac-pY-Q-N-NH2 Tripeptide Mimic
3imj	Crystal Structure of the Grb2 SH2 Domain in Complex with a Cyclopropyl-constrained Ac-pTyr-Ile-Asn-NH2 Tripeptide Mimic
3in7	Crystal Structure of the Grb2 SH2 Domain in Complex with a Cyclopropyl-constrained Ac-pY-Q-N-NH2 Tripeptide Mimic
3in8	Crystal Structure of the Grb2 SH2 Domain in Complex with a Flexible Ac-pTyr-Ile-Asn-NH2 Tripeptide Mimic
3k2m	Crystal Structure of Monobody HA4/Abl1 SH2 Domain Complex
3kfj	Crystal Structure of the Grb2 SH2 Domain in Complex with a Flexible Ac-pY-E-N-NH2 Tripeptide Mimic
3m7f	Crystal structure of the Nedd4 C2/Grb10 SH2 complex
3maz	Crystal Structure of the Human BRDG1/STAP-1 SH2 Domain in Complex with the NTAL pTyr136 Peptide
3mxc	Structures of Grb2-SH2 Domain and AICD peptide Complexes Reveal a Conformational Switch and Their Functional Implications.
3mxy	Structures of Grb2-SH2 Domain and AICD peptide Complexes Reveal a Conformational Switch and Their Functional Implications.
3n7y	Crystal Structure of the Grb2 SH2 Domain in Complex with a 20-Membered Macrocyclic Ligand Having the Sequence pYVNV
3n84	Crystal Structure of the Grb2 SH2 Domain in Complex with a 23-Membered Macrocyclic Ligand Having the Sequence pYVNVP
3n8m	Crystal Structure of the Grb2 SH2 Domain in Complex with An Acyclic Ligand Having the Sequence pYVNVP
3nhn	Crystal structure of the SRC-family kinase HCK SH3-SH2-linker regulatory region
3ov1	Crystal Structure of the Grb2 SH2 Domain in Complex with a pYXN-Derived Tripeptide
3ove	Crystal Structure of the Grb2 SH2 Domain in Complex with a pYXN-Derived Tripeptide
3pfv	Crystal structure of Cbl-b TKB domain in complex with EGFR pY1069 peptide
3pjp	A Tandem SH2 Domain in Transcription Elongation Factor Spt6 Binds the Phosphorylated RNA Polymerase II C-terminal Repeat Domain(CTD)
3pqz	Grb7 SH2 with peptide
3ps5	Crystal structure of the full-length Human Protein Tyrosine Phosphatase SHP-1
3psi	Crystal Structure of the Spt6 core domain from Saccharomyces cerevisiae, Form Spt6(239-1451)
3psj	Crystal Structure of the Spt6 Tandem SH2 Domain from Saccharomyces cerevisiae, Form Se-Spt6 (1247-1451)
3psk	Crystal Structure of the Spt6 Tandem SH2 Domain from Saccharomyces cerevisiae, Form Native Spt6 (1247-1451)
3qwx	CED-2 1-174
3qwy	CED-2
3s8l	Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing Hydrophobic Surface Area
3s8n	Crystal Structure of the Grb2 SH2 Domain in Complex with a pYXN-Derived Tripeptide
3s8o	Crystal Structure of the Grb2 SH2 Domain in Complex with a pYXN-Derived Tripeptide
3s9k	Crystal structure of the Itk SH2 domain.
3t04	Crystal structure of monobody 7c12/abl1 sh2 domain complex
3tkz	Structure of the SHP-2 N-SH2 domain in a 1:2 complex with RVIpYFVPLNR peptide
3tl0	Structure of SHP2 N-SH2 domain in complex with RLNpYAQLWHR peptide
3uf4	Crystal structure of a SH3 and SH2 domains of FYN protein (Proto-concogene Tyrosine-protein kinase Fyn) from Mus musculus at 1.98 A resolution
3us4	Crystal structure of a SH2 domain of a megakaryocyte-associated tyrosine kinase (MATK) from Homo sapiens at 1.50 A resolution
3uyo	Crystal structure of monobody SH13/ABL1 SH2 domain complex
3vgo	Crystal structure of the N-terminal fragment of Cbl-b
3vry	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-cyclopentane
3vrz	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]-3-benzylurea
3vs0	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]benzamide
3vs1	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]-3-phenylurea
3vs2	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 7-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
3vs3	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
3vs4	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 5-(4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
3vs5	Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 7-(1-methylpiperidin-4-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
3vs6	Crystal structure of HCK complexed with a pyrazolo-pyrimidine inhibitor tert-butyl {4-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate
3vs7	Crystal structure of HCK complexed with a pyrazolo-pyrimidine inhibitor 1-cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
3wa4	Grb2 SH2 domain/CD28-derived peptide complex
3zni	Structure of phosphoTyr363-Cbl-b - UbcH5B-Ub - ZAP-70 peptide complex
4a55	Crystal structure of p110alpha in complex with iSH2 of p85alpha and the inhibitor PIK-108
4d8k	Crystal structure of a SH3-SH2 domains of a lymphocyte-specific protein tyrosine kinase (LCK) from Homo sapiens at 2.36 A resolution
4dgp	The wild-type Src homology 2 (SH2)-domain containing protein tyrosine phosphatase-2 (SHP2)
4dgx	LEOPARD Syndrome-Associated SHP2/Y279C mutant
4e68	Unphosphorylated STAT3B core protein binding to dsDNA
4e93	Crystal structure of human Feline Sarcoma Viral Oncogene Homologue (v-FES)in complex with TAE684
4eih	Crystal structure of Arg SH2 domain
4ey0	Structure of tandem SH2 domains from PLCgamma1
4f59	Triple mutant Src SH2 domain
4f5a	Triple mutant Src SH2 domain bound to phosphate ion
4f5b	Triple mutant Src SH2 domain bound to phosphotyrosine
4fbn	Insights into structural integration of the PLCgamma regulatory region and mechanism of autoinhibition and activation based on key roles of SH2 domains
4fl2	Structural and Biophysical Characterization of the Syk Activation Switch
4fl3	Structural and Biophysical Characterization of the Syk Activation Switch
4gl9	Crystal structure of inhibitory protein SOCS3 in complex with JAK2 kinase domain and fragment of GP130 intracellular domain
4gwf	Crystal structure of the tyrosine phosphatase SHP-2 with Y279C mutation
4h1o	Crystal structure of the tyrosine phosphatase SHP-2 with D61G mutation
4h34	Crystal structure of the tyrosine phosphatase SHP-2 with Q506P mutation
4je4	Crystal Structure of Monobody NSa1/SHP2 N-SH2 Domain Complex
4jeg	Crystal Structure of Monobody CS1/SHP2 C-SH2 Domain Complex
4jgh	Structure of the SOCS2-Elongin BC complex bound to an N-terminal fragment of Cullin5
4jmg	Crystal structure of the synthetic protein in complex with pY peptide
4jmh	Crystal structure of synthetic protein in complex with double pY peptide
4jps	Co-crystal Structures of the Lipid Kinase PI3K alpha with Pan and Isoform Selective Inhibitors
4k11	The structure of 1NA in complex with Src T338G
4k2r	Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker
4k44	Auto-inhibition and phosphorylation-induced activation of PLC-gamma isozymes
4k45	Auto-inhibition and phosphorylation-induced activation of PLC-gamma isozymes
4l1b	Crystal Structure of p110alpha complexed with niSH2 of p85alpha
4l23	Crystal Structure of p110alpha complexed with niSH2 of p85alpha and PI-103
4l2y	Crystal Structure of p110alpha complexed with niSH2 of p85alpha and compound 9d
4lud	Crystal Structure of HCK in complex with the fluorescent compound SKF86002
4lue	Crystal Structure of HCK in complex with 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (resulting from displacement of SKF86002)
4m4z	SH3 and SH2 domains of human Src-like adaptor protein 2 (SLAP2)
4nwf	4NWF
4nwg	4NWG
4ohd	4OHD
4ohe	4OHE
4ohh	4OHH
4ohi	4OHI
4ohl	4OHL
4ovu	4OVU
4ovv	4OVV
4p9v	4P9V
4p9z	4P9Z
4po6	Crystal structure of the human TYK2 FERM and SH2 domains with an IFNAR1 intracellular peptide
4qsy	4QSY
4roj	4ROJ
4tzi	4TZI
4u17	4U17
4u1p	4U1P
4u5w	4U5W
4waf	4WAF
4wwq	4WWQ
4x6s	4X6S
4xey	4XEY
4xi2	4XI2
4xz0	4XZ0
4xz1	4XZ1
4y5u	4Y5U
4y5w	4Y5W
4ykn	4YKN
4z32	4Z32
4zop	4ZOP
5aul	5AUL
5bo4	5BO4
5cdw	5CDW
5d0j	5D0J
5d39	5D39
5dc0	5DC0
5dc4	5DC4
5dc9	5DC9
5df6	5DF6
5eel	5EEL
5eeq	5EEQ
5eg3	5EG3
5ehp	5EHP
5ehr	5EHR
5fi4	5FI4
5i6v	5I6V
5ibm	5IBM
5ibs	5IBS
5itd	5ITD
5ixd	5IXD
5ixi	5IXI
5l04	5L04

Links (links to other resources describing this domain)

• PROSITE: SH2
• PFAM: SH2
• INTERPRO: IPR000980