SH3

Src homology 3 domains

• SMART accession number: SM00326
• Description: Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.
• Interpro abstract (IPR001452): SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues [(PUBMED:15335710), (PUBMED:11256992)]. They are found in a great variety of intracellular or membrane-associated proteins [(PUBMED:1639195), (PUBMED:14731533), (PUBMED:7531822)] for example, in a variety of proteins with enzymatic activity, in adaptor proteins that lack catalytic sequences and in cytoskeletal proteins, such as fodrin and yeast actin binding protein ABP-1.

  The SH3 domain has a characteristic fold which consists of five or six beta-strands arranged as two tightly packed anti-parallel beta sheets. The linker regions may contain short helices []. The surface of the SH3-domain bears a flat, hydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions. The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins, altering their subcellular location and mediating the assembly of large multiprotein complexes [(PUBMED:7953536)].

  The crystal structure of the SH3 domain of the cytoskeletal protein spectrin, and the solution structures of SH3 domains of phospholipase C (PLC-y) and phosphatidylinositol 3-kinase p85 alpha-subunit, have been determined [(PUBMED:1279434), (PUBMED:7684655), (PUBMED:7681365)]. In spite of relatively limited sequence similarity, their overall structures are similar. The domains belong to the alpha+beta structural class, with 5 to 8 beta-strands forming 2 tightly-packed, anti-parallel beta-sheets arranged in a barrel-like structure, and intervening loops sometimes forming helices. Conserved aliphatic and aromatic residues form a hydrophobic core (A11, L23, A29, V34, W42, L52 and V59 in PLC-y [(PUBMED:7681365)]) and a hydrophobic pocket on the molecular surface (L12, F13, W53 and P55 in PLC-y). The conserved core is believed to stabilise the fold, while the pocket is thought to serve as a binding site for target proteins. Conserved carboxylic amino acids located in the loops, on the periphery of the pocket (D14 and E22), may be involved in protein-protein interactions via proline-rich regions. The N- and C-termini are packed in close proximity, indicating that they are independent structural modules.

• GO function: protein binding (GO:0005515)

There are 16239 SH3 domains in 12607 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Cellular role: signalling
Binding / catalysis: protein-binding, proline-rich peptide-binding

Literature (relevant references for this domain)

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

• 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.

• Cowburn D
• Peptide recognition by PTB and PDZ domains.
• Curr Opin Struct Biol. 1997; 7: 835-8

Protein tyrosine binding (PTB) and 'post synaptic density disc-large zo-1' (PDZ) domains bind to short peptidic ligands by augmentation of one of the domain's beta sheets and other recognition mechanisms. The two domain classes have a superficial resemblance to each other, even though no sequential homology exists. The structural bases of the interactions are well understood for the few domains now experimentally determined, and ligand-target pairs can probably be identified in favorable cases by analogy with the known domains. For both PTB and PDZ classes, functional activities are still not fully defined: it is possible that these domain classes, along with pleckstrin homology domains, have multiple roles.

• Han L et al.
• Protein binding and signaling properties of RIN1 suggest a unique effector function.
• Proc Natl Acad Sci U S A. 1997; 94: 4954-9

Human RIN1 was first characterized as a RAS binding protein based on the properties of its carboxyl-terminal domain. We now show that full-length RIN1 interacts with activated RAS in mammalian cells and defines a minimum region of 434 aa required for efficient RAS binding. RIN1 interacts with the "effector domain" of RAS and employs some RAS determinants that are common to, and others that are distinct from, those required for the binding of RAF1, a known RAS effector. The same domain of RIN1 that binds RAS also interacts with 14-3-3 proteins, extending the similarity between RIN1 and other RAS effectors. When expressed in mammalian cells, the RAS binding domain of RIN1 can act as a dominant negative signal transduction blocker. The amino-terminal domain of RIN1 contains a proline-rich sequence similar to consensus Src homology 3 (SH3) binding regions. This RIN1 sequence shows preferential binding to the ABL-SH3 domain in vitro. Moreover, the amino-terminal domain of RIN1 directly associates with, and is tyrosine phosphorylated by, c-ABL. In addition, RIN1 encodes a functional SH2 domain that has the potential to activate downstream signals. These data suggest that RIN1 is able to mediate multiple signals. A differential pattern of expression and alternate splicing indicate several levels of RIN1 regulation.

• Hildebrandt F et al.
• A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1.
• Nat Genet. 1997; 17: 149-53

Juvenile nephronophthisis (NPH), an autosomal recessive cystic kidney disease, is the primary genetic cause of chronic renal failure in children. About two thirds of patients with NPH carry a large homozygous deletion at the gene locus NPH1 on 2q13. We here identify a novel gene. NPHP1, which extends over most of this common deletion. The 4.5-kb transcript encodes a protein with an SH3 domain, which is highly conserved throughout evolution. The 11-kb interval between the 3' end of NPHP1 and an inverted repeat containing the distal deletion breakpoint was found to contain the first exon of a second gene, MALL. In patients with a hemizygous deletion of the NPH1 region, additional point mutations were found in NPHP1 but not in MALL.

• 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.

• 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.

• 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.

• Mott HR, Carpenter JW, Zhong S, Ghosh S, Bell RM, Campbell SL
• The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site.
• Proc Natl Acad Sci U S A. 1996; 93: 8312-7

The Raf-1 protein kinase is the best-characterized downstream effector of activated Ras. Interaction with Ras leads to Raf-1 activation and results in transduction of cell growth and differentiation signals. The details of Raf-1 activation are unclear, but our characterization of a second Ras-binding site in the cysteine-rich domain (CRD) and the involvement of both Ras-binding sites in effective Raf-1-mediated transformation provides insight into the molecular aspects and consequences of Ras-Raf interactions. The Raf-1 CRD is a member of an emerging family of domains, many of which are found within signal transducing proteins. Several contain binding sites for diacylglycerol (or phorbol esters) and phosphatidylserine and are believed to play a role in membrane translocation and enzyme activation. The CRD from Raf-1 does not bind diacylglycerol but interacts with Ras and phosphatidylserine. To investigate the ligand-binding specificities associated with CRDs, we have determined the solution structure of the Raf-1 CRD using heteronuclear multidimensional NMR. We show that there are differences between this structure and the structures of two related domains from protein kinase C (PKC). The differences are confined to regions of the CRDs involved in binding phorbol ester in the PKC domains. Since phosphatidylserine is a common ligand, we expect its binding site to be located in regions where the structures of the Raf-1 and PKC domains are similar. The structure of the Raf-1 CRD represents an example of this family of domains that does not bind diacylglycerol and provides a framework for investigating its interactions with other molecules.

• Muchmore SW et al.
• X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death.
• Nature. 1996; 381: 335-41

THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures consist of two central, primarily hydrophobic alpha-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices alpha1 and alpha2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the alpha-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.

• Musacchio A, Cantley LC, Harrison SC
• Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit.
• Proc Natl Acad Sci U S A. 1996; 93: 14373-8

Proteins such as the product of the break-point cluster region, chimaerin, and the Src homology 3-binding protein 3BP1, are GTPase activating proteins (GAPs) for members of the Rho subfamily of small GTP-binding proteins (G proteins or GTPases). A 200-residue region, named the breakpoint cluster region-homology (BH) domain, is responsible for the GAP activity. We describe here the crystal structure of the BH domain from the p85 subunit of phosphatidylinositol 3-kinase at 2.0 A resolution. The domain is composed of seven helices, having a previously unobserved arrangement. A core of four helices contains most residues that are conserved in the BH family. Their packing suggests the location of a G-protein binding site. This structure of a GAP-like domain for small GTP-binding proteins provides a framework for analyzing the function of this class of molecules.

• Sparks AB, Hoffman NG, McConnell SJ, Fowlkes DM, Kay BK
• Cloning of ligand targets: systematic isolation of SH3 domain-containing proteins.
• Nat Biotechnol. 1996; 14: 741-4

Based on the prevalence of modular protein domains, such as Src homology domain 3 and 2 (SH3 and SH2), among important signaling molecules, we have sought to identify new SH3 domain-containing proteins. However, modest sequence similarity among these domains restricts the use of DNA-based methods for this purpose. To circumvent this limitation, we have developed a functional screen that permits the rapid cloning of modular domains based on their ligand-binding activity. Using operationally defined SH3 ligands from combinatorial peptide libraries, we screened a series of mouse and human cDNA expression libraries. We found that 69 of the 74 clones isolated encode at least one SH3 domain. These clones encode 18 different SH3-containing proteins, 10 of which have not been described previously. The isolation of entire repertoires of modular domain-containing proteins will prove invaluable in genome analysis and in bringing new targets into drug discovery programs.

• 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.

• Feng S, Kasahara C, Rickles RJ, Schreiber SL
• Specific interactions outside the proline-rich core of two classes of Src homology 3 ligands.
• Proc Natl Acad Sci U S A. 1995; 92: 12408-15

Two dodecapeptides belonging to distinct classes of Src homology 3 (SH3) ligands and selected from biased phage display libraries were used to investigate interactions between a specificity pocket in the Src SH3 domain and ligant residues flanking the proline-rich core. The solution structures of c-Src SH3 complexed with these peptides were solved by NMR. In addition to proline-rich, polyproline type II helix-forming core, the class I and II ligands each possesses a flanking sequence that occupies a large pocket between the RT and n-Src loops of the SH3 domain. Structural and mutational analyses illustrate how the two classes of SH3 ligands exploit a specificity pocket on the receptor differently to increase binding affinity and specificity.

• 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.

• 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.

• 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)

• 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.

• 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.

• 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.

• Perez-Alvarado GC et al.
• Structure of the carboxy-terminal LIM domain from the cysteine rich protein CRP.
• Nat Struct Biol. 1994; 1: 388-98

The three dimensional solution structure of the carboxy terminal LIM domain of the avian Cysteine Rich Protein (CRP) has been determined by nuclear magnetic resonance spectroscopy. The domain contains two zinc atoms bound independently in CCHC (C = Cys, H = His) and CCCC modules. Both modules contain two orthogonally-arranged antiparallel beta-sheets, and the CCCC module contains an alpha-helix at its C terminus. The modules pack due to hydrophobic interactions forming a novel global fold. The structure of the C-terminal CCCC module is essentially identical to that observed for the DNA-interactive CCCC modules of the GATA-1 and steroid hormone receptor DNA binding domains, raising the possibility that the LIM motif may have a DNA binding function.

• 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)

• Yu H, Chen JK, Feng S, Dalgarno DC, Brauer AW, Schreiber SL
• Structural basis for the binding of proline-rich peptides to SH3 domains.
• Cell. 1994; 76: 933-45

A common RXL motif was found in proline-rich ligands that were selected from a biased combinatorial peptide library on the basis of their ability to bind specifically to the SH3 domains from phosphatidylinositol 3-kinase (PI3K) or c-Src. The solution structure of the PI3K SH3 domain complexed to one of these ligands, RKLPPRPSK (RLP1), was determined. Structure-based mutations were introduced into the PI3K SH3 domain and the RLP1 ligand, and the influence of these mutations on binding was evaluated. We conclude that SH3 domains recognize proline-rich motifs possessing the left-handed type II polyproline (PPII) helix conformation. Two proline residues directly contact the receptor. Other prolines in the ligands appear to function as a molecular scaffold, promoting the formation of the PPII helix. Three nonproline residues consisting of combinations of arginine and leucine interact extensively with the SH3 domain and appear to confer ligand specificity.

• 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.

• 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.

• Ren R, Mayer BJ, Cicchetti P, Baltimore D
• Identification of a ten-amino acid proline-rich SH3 binding site.
• Science. 1993; 259: 1157-61

The Src homology 3 (SH3) region is a small protein domain present in a very large group of proteins, including cytoskeletal elements and signaling proteins. It is believed that SH3 domains serve as modules that mediate protein-protein associations and, along with Src homology 2 (SH2) domains, regulate cytoplasmic signaling. The SH3 binding sites of two SH3 binding proteins were localized to a nine- or ten-amino acid stretch very rich in proline residues. Similar SH3 binding motifs exist in the formins, proteins that function in pattern formation in embryonic limbs of the mouse, and one subtype of the muscarinic acetylcholine receptor. Identification of the SH3 binding site provides a basis for understanding the interaction between the SH3 domains and their targets.

• 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.

• Weir HM, Kraulis PJ, Hill CS, Raine AR, Laue ED, Thomas JO
• Structure of the HMG box motif in the B-domain of HMG1.
• EMBO J. 1993; 12: 1311-9

The conserved, abundant chromosomal protein HMG1 consists of two highly homologous, folded, basic DNA-binding domains, each of approximately 80 amino acid residues, and an acidic C-terminal tail. Each folded domain represents an 'HMG box', a sequence motif recently recognized in certain sequence-specific DNA-binding proteins and which also occurs in abundant HMG1-like proteins that bind to DNA without sequence specificity. The HMG box is defined by a set of highly conserved residues (most distinctively aromatic and basic) and appears to define a novel DNA-binding structural motif. We have expressed the HMG box region of the B-domain of rat HMG1 (residues 88-164 of the intact protein) in Escherichia coli and we describe here the determination of its structure by 2D 1H-NMR spectroscopy. There are three alpha-helices (residues 13-29, 34-48 and 50-74), which together account for approximately 75% of the total residues and contain many of the conserved basic and aromatic residues. Strikingly, the molecule is L-shaped, the angle of approximately 80 degrees between the two arms being defined by a cluster of conserved, predominantly aromatic, residues. The distinctive shape of the HMG box motif, which is distinct from hitherto characterized DNA-binding motifs, may be significant in relation to its recognition of four-way DNA junctions.

• 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.

• 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.

• Otsu M et al.
• Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase.
• Cell. 1991; 65: 91-104

Affinity-purified bovine brain phosphatidylinositol 3-kinase (PI3-kinase) contains two major proteins of 85 and 110 kd. Amino acid sequence analysis and cDNA cloning reveals two related 85 kd proteins (p85 alpha and p85 beta), which both contain one SH3 and two SH2 regions (src homology regions). When expressed, these 85 kd proteins bind to and are substrates for tyrosine-phosphorylated receptor kinases and the polyoma virus middle-T antigen/pp60c-src complex, but lack PI3-kinase activity. However, an antiserum raised against p85 beta immunoprecipitates PI3-kinase activity. The active PI3-kinase complex containing p85 alpha or p85 beta and the 110 kd protein binds to PDGF but not EGF receptors. p85 alpha and p85 beta may mediate specific PI3-kinase interactions with a subset of tyrosine kinases.

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

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the SH3 domain.

Protein	Disease
Myosin-VIIa (Q13402) (SMART)	OMIM:276903: Usher syndrome, type 1B ; Deafness, autosomal recessive 2, neurosensory OMIM:600060: Deafness, autosomal dominant 11, neurosensory OMIM:601317:
Peroxisomal membrane protein PEX13 (Q92968) (SMART)	OMIM:601789: Zellweger syndrome OMIM:214100: Adrenoleukodystrophy, neonatal OMIM:202370:

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
5.36	map04012	ErbB signaling pathway
5.14	map04660	T cell receptor signaling pathway
5.08	map04670	Leukocyte transendothelial migration
5.02	map04010	MAPK signaling pathway
4.85	map04810	Regulation of actin cytoskeleton
4.63	map04664	Fc epsilon RI signaling pathway
4.51	map04510	Focal adhesion
4.12	map04530	Tight junction
3.95	map04650	Natural killer cell mediated cytotoxicity
3.72	map04360	Axon guidance
2.82	map05120	Epithelial cell signaling in Helicobacter pylori infection
2.82	map04910	Insulin signaling pathway
2.77	map04662	B cell receptor signaling pathway
2.71	map05220	Chronic myeloid leukemia
2.60	map04520	Adherens junction
2.54	map04630	Jak-STAT signaling pathway
2.26	map05214	Glioma
2.26	map05223	Non-small cell lung cancer
2.26	map05211	Renal cell carcinoma
2.20	map04370	VEGF signaling pathway
1.75	map04070	Phosphatidylinositol signaling system
1.47	map04540	Gap junction
1.41	map05213	Endometrial cancer
1.41	map05221	Acute myeloid leukemia
1.41	map05210	Colorectal cancer
1.41	map05215	Prostate cancer
1.30	map05212	Pancreatic cancer
1.07	map04912	GnRH signaling pathway
1.07	map05040	Huntington's disease
0.90	map00562	Inositol phosphate metabolism
0.85	map04210	Apoptosis
0.85	map04930	Type II diabetes mellitus
0.85	map04914	Progesterone-mediated oocyte maturation
0.85	map05222	Small cell lung cancer
0.85	map04020	Calcium signaling pathway
0.85	map04620	Toll-like receptor signaling pathway
0.85	map04150	mTOR signaling pathway
0.85	map05218	Melanoma
0.56	map01030	Glycan structures - biosynthesis 1
0.56	map04320	Dorso-ventral axis formation
0.56	map04730	Long-term depression
0.56	map00510	N-Glycan biosynthesis
0.56	map00533	Keratan sulfate biosynthesis
0.45	map04110	Cell cycle
0.40	map00350	Tyrosine metabolism
0.40	map00340	Histidine metabolism
0.40	map05050	Dentatorubropallidoluysian atrophy (DRPLA)
0.34	map00230	Purine metabolism
0.28	map00642	Ethylbenzene degradation
0.28	map00632	Benzoate degradation via CoA ligation
0.28	map00564	Glycerophospholipid metabolism
0.28	map00360	Phenylalanine metabolism
0.28	map00903	Limonene and pinene degradation
0.28	map00960	Alkaloid biosynthesis II
0.28	map00310	Lysine degradation
0.28	map03320	PPAR signaling pathway
0.28	map00624	1- and 2-Methylnaphthalene degradation
0.28	map00550	Peptidoglycan biosynthesis
0.11	map00150	Androgen and estrogen metabolism
0.11	map00626	Naphthalene and anthracene degradation
0.11	map00380	Tryptophan metabolism
0.11	map00440	Aminophosphonate metabolism
0.11	map00450	Selenoamino acid metabolism
0.06	map04610	Complement and coagulation cascades
0.06	map00511	N-Glycan degradation
0.06	map02010	ABC transporters - General
0.06	map01032	Glycan structures - degradation

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 SH3 domain which could be assigned to a KEGG orthologous group, and not all proteins containing SH3 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 SH3 domains in PDB

PDB code	Title
1a0n	Nmr study of the sh3 domain from fyn proto-oncogene tyrosine kinase complexed with the synthetic peptide p2l corresponding to residues 91-104 of the p85 subunit of pi3- kinase, family of 25 structures
1abo	Crystal structure of the complex of the abl tyrosine kinase sh3 domain with 3bp-1 synthetic peptide
1abq	Crystal structure of the unliganded abl tyrosine kinase sh3 domain
1ad5	Src family kinase hck-amp-pnp complex
1aey	Alpha-spectrin src homology 3 domain, solution nmr, 15 structures
1aoj	The sh3 domain of eps8 exists as a novel intertwined dimer
1ark	Sh3 domain from human nebulin, nmr, 15 structures
1avz	V-1 nef protein in complex with wild type fyn sh3 domain
1awj	Intramolecular itk-proline complex, nmr, minimized average structure
1awo	The solution nmr structure of abl sh3 and its relationship to sh2 in the sh(32) construct, 20 structures
1aww	Sh3 domain from bruton's tyrosine kinase, nmr, 42 structures
1awx	Sh3 domain from bruton's tyrosine kinase, nmr, minimized average structure
1aze	Nmr structure of the complex between the c32s-y7v mutant of the nsh3 domain of grb2 with a peptide from sos, 10 structures
1azg	Nmr study of the sh3 domain from fyn proto-oncogene tyrosine kinase kinase complexed with the synthetic peptide p2l corresponding to residues 91-104 of the p85 subunit of pi3-kinase, minimized average (probmap) structure
1b07	Crk sh3 domain complexed with peptoid inhibitor
1bb9	Crystal structure of the sh3 domain from rat amphiphysin 2
1bbz	Crystal structure of the abl-sh3 domain complexed with a designed high-affinity peptide ligand: implications for sh3-ligand interactions
1bk2	A-spectrin sh3 domain d48g mutant
1bu1	Src family kinase hck sh3 domain
1cka	Structural basis for the specific interaction of lysine- containing proline-rich peptides with the n-terminal sh3 domain of c-crk
1ckb	Structural basis for the specific interaction of lysine- containing proline-rich peptides with the n-terminal sh3 domain of c-crk
1csk	The crystal structure of human csksh3: structural diversity near the rt-src and n-src loop
1e6g	A-spectrin sh3 domain a11v, v23l, m25i, v53i, v58l mutant
1e6h	A-spectrin sh3 domain a11v, m25i, v44i, v58l mutants
1e7o	A-spectrin sh3 domain a11v, v23l, m25v, v44i, v58l mutations
1efn	Hiv-1 nef protein in complex with r96i mutant fyn sh3 domain
1fmk	Crystal structure of human tyrosine-protein kinase c-src
1fyn	Phosphotransferase
1g2b	Alpha-spectrin src homology 3 domain, circular permutant, cut at n47-d48
1g83	Crystal structure of fyn sh3-sh2
1gbq	Solution nmr structure of the grb2 n-terminal sh3 domain complexed with a ten-residue peptide derived from sos direct refinement against noes, j-couplings, and 1h and 13c chemical shifts, minimized average structure
1gbr	Orientation of peptide fragments from sos proteins bound to the n-terminal sh3 domain of grb2 determined by nmr spectroscopy
1gcp	Crystal structure of vav sh3 domain
1gcq	Crystal structure of vav and grb2 sh3 domains
1gfc	Solution structure and ligand-binding site of the c- terminal sh3 domain of grb2
1gfd	Solution structure and ligand-binding site of the c- terminal sh3 domain of grb2
1gl5	Nmr structure of the sh3 domain from the tec protein tyrosine kinase
1gri	Grb2
1h3h	Structural basis for specific recognition of an rxxk-containing slp-76 peptide by the gads c-terminal sh3 domain
1h8k	A-spectrin sh3 domain a11v, v23l, m25v, v53i, v58l mutant
1h92	Sh3 domain of human lck tyrosine kinase
1hd3	A-spectrin sh3 domain f52y mutant
1hjd	Melanoma inhibitory activity (mia) protein
1hsq	Solution structure of the sh3 domain of phospholipase cgamma
1i07	Eps8 sh3 domain intertwined dimer
1i0c	Eps8 sh3 closed monomer
1i1j	Structure of melanoma inhibitory activity protein: a member of a new family of secreted proteins
1io6	Growth factor receptor-bound protein 2 (grb2) c-terminal sh3 domain complexed with a ligand peptide (nmr, minimized mean structure)
1j3t	Solution structure of the second sh3 domain of human intersectin 2 (kiaa1256)
1jeg	Solution structure of the sh3 domain from c-terminal src kinase complexed with a peptide from the tyrosine phosphatase pep
1jo8	Structural analysis of the yeast actin binding protein abp1 sh3 domain
1jqq	Crystal structure of pex13p(301-386) sh3 domain
1ju5	Ternary complex of an crk sh2 domain, crk-derived phophopeptide, and abl sh3 domain by nmr spectroscopy
1jxm	Crystal structure of the gmp bound sh3-hook-gk fragment of psd-95
1jxo	Crystal structure of the sh3-hook-gk fragment of psd-95
1k0x	Solution structure of melanoma inhibitory activity protein
1k1z	Solution structure of n-terminal sh3 domain mutant(p33g) of murine vav
1k4u	Solution structure of the c-terminal sh3 domain of p67phox complexed with the c-terminal tail region of p47phox
1k76	Solution structure of the c-terminal sem-5 sh3 domain (minimized average structure)
1k9a	Crystal structure analysis of full-length carboxyl-terminal src kinase at 2.5 a resolution
1kfz	Solution structure of c-terminal sem-5 sh3 domain (ensemble of 16 structures)
1kik	Sh3 domain of lymphocyte specific kinase (lck)
1kjw	Sh3-guanylate kinase module from psd-95
1ksw	Structure of human c-src tyrosine kinase (thr338gly mutant) in complex with n6-benzyl adp
1lck	Sh3-sh2 domain fragment of human p56-lck tyrosine kinase complexed with the 10 residue synthetic phosphotyrosyl peptide tegqpyqpqpa
1m27	Crystal structure of sap/fynsh3/slam ternary complex
1m30	Solution structure of n-terminal sh3 domain from oncogene protein c-crk
1m3a	Solution structure of a circular form of the truncated n- terminal sh3 domain from oncogene protein c-crk.
1m3b	Solution structure of a circular form of the n-terminal sh3 domain (a134c, e135g, r191g mutant) from oncogene protein c-crk.
1m3c	Solution structure of a circular form of the n-terminal sh3 domain (e132c, e133g, r191g mutant) from oncogene protein c-crk
1m8m	Solid-state mas nmr structure of the a-spectrin sh3 domain
1muz	Nmr structure of the tumor suppressor bin1: alternative splicing in melanoma and interaction with c-myc
1mv0	Nmr structure of the tumor suppressor bin1: alternative splicing in melanoma and interaction with c-myc
1mv3	Nmr structure of the tumor suppressor bin1: alternative splicing in melanoma and interaction with c-myc
1n5z	Complex structure of pex13p sh3 domain with a peptide of pex14p
1neb	Sh3 domain from human nebulin, nmr, minimized average structure
1neg	Crystal structure analysis of n-and c-terminal labeled sh3- domain of alpha-chicken spectrin
1ng2	Structure of autoinhibited p47phox
1nlo	Structure of signal transduction protein, nmr, minimized average structure
1nlp	Structure of signal transduction protein, nmr, minimized average structure
1nm7	Solution structure of the scpex13p sh3 domain
1nyf	Nmr study of the sh3 domain from fyn proto-oncogene tyrosine kinase, minimized average (probmap) structure
1nyg	Nmr study of the sh3 domain from fyn proto-oncogene tyrosine kinase, family of 20 structures
1oeb	Mona/gads sh3c domain
1oot	Crystal structure of the sh3 domain from a s. cerevisiae hypothetical 40.4 kda protein at 1.39 a resolution
1opk	Structural basis for the auto-inhibition of c-abl tyrosine kinase
1opl	Structural basis for the auto-inhibition of c-abl tyrosine kinase
1ov3	Structure of the p22phox-p47phox complex
1pht	Phosphatidylinositol 3-kinase p85-alpha subunit sh3 domain, residues 1-85
1pks	Structure of the pi3k sh3 domain and analysis of the sh3 family
1pkt	Structure of the pi3k sh3 domain and analysis of the sh3 family
1pnj	Solution structure and ligand-binding site of the sh3 domain of the p85alpha subunit of phosphatidylinositol 3- kinase
1prl	Two binding orientations for peptides to src sh3 domain: development of a general model for sh3-ligand interactions
1prm	Two binding orientations for peptides to src sh3 domain: development of a general model for sh3-ligand interactions
1pwt	Thermodynamic analysis of alpha-spectrin sh3 and two of its circular permutants with different loop lengths: discerning the reasons for rapid folding in proteins
1qcf	Crystal structure of hck in complex with a src family- selective tyrosine kinase inhibitor
1qkw	Alpha-spectrin src homology 3 domain, n47g mutant in the distal loop.
1qkx	Alpha-spectrin src homology 3 domain, n47a mutant in the distal loop.
1qly	Nmr study of the sh3 domain from bruton's tyrosine kinase, structures
1qwe	C-src sh3 domain complexed with ligand app12
1qwf	C-src sh3 domain complexed with ligand vsl12
1ri9	Structure of a helically extended sh3 domain of the t cell adapter protein adap
1rlp	Two binding orientations for peptides to src sh3 domain: development of a general model for sh3-ligand interactions
1rlq	Two binding orientations for peptides to src sh3 domain: development of a general model for sh3-ligand interactions
1ruw	Crystal structure of the sh3 domain from s. cerevisiae myo3
1s1n	Sh3 domain of human nephrocystin
1sem	Structural determinants of peptide-binding orientation and of sequence specificity in sh3 domains
1shf	Crystal structure of the sh3 domain in human fyn; comparison of the three-dimensional structures of sh3 domains in tyrosine kinases and spectrin
1shg	Crystal structure of a src-homology 3 (sh3) domain
1spk	Solution structure of rsgi ruh-010, an sh3 domain from mouse cdna
1srl	1h and 15n assignments and secondary structure of the src sh3 domain
1srm	1h and 15n assignments and secondary structure of the src sh3 domain
1ssh	Crystal structure of the sh3 domain from a s. cerevisiae hypothetical 40.4 kda protein in complex with a peptide
1t0h	Crystal structure of the rattus norvegicus voltage gated calcium channel beta subunit isoform 2a
1t0j	Crystal structure of a complex between voltage-gated calcium channel beta2a subunit and a peptide of the alpha1c subunit
1t3l	Structural analysis of the voltage-dependent calcium channel beta subunit functional core in complex with alpha1 interaction domain
1t3s	Structural analysis of the voltage-dependent calcium channel beta subunit functional core
1tg0	0.97-a structure of the sh3 domain of bbc1
1tuc	Alpha-spectrin src homology 3 domain, circular permutant, cut at s19-p20
1tud	Alpha-spectrin src homology 3 domain, circular permutant, cut at n47-d48
1u06	Crystal structure of chicken alpha-spectrin sh3 domain
1u3o	Solution structure of rat kalirin n-terminal sh3 domain
1u5s	Nmr structure of the complex between nck-2 sh3 domain and pinch-1 lim4 domain
1udl	The solution structure of the fifth sh3 domain of intersectin 2 (kiaa1256)
1ue9	Solution structure of the fourth sh3 domain of human intersectin 2 (kiaa1256)
1uec	Crystal structure of autoinhibited form of tandem sh3 domain of p47phox
1uff	Solution structure of the first sh3 domain of human intersectin2 (kiaa1256)
1ug1	Sh3 domain of hypothetical protein baa76854.1
1ugv	Solution structure of the sh3 domain of human olygophrein-1 like protein (kiaa0621)
1uhc	Solution structure of rsgi ruh-002, a sh3 domain of kiaa1010 protein [homo sapiens]
1uhf	Solution structure of the third sh3 domain of human intersectin 2(kiaa1256)
1uj0	Crystal structure of stam2 sh3 domain in complex with a ubpy-derived peptide
1ujy	Solution structure of sh3 domain in rac/cdc42 guanine nucleotide exchange factor(gef) 6
1uti	Mona/gads sh3c in complex with hpk derived peptide
1uue	A-spectrin sh3 domain (v44t, d48g mutant)
1v1c	Solution structure of the sh3 domain of obscurin
1va7	Yeast myo3 sh3 domain, triclinic crystal form
1vyt	Beta3 subunit complexed with aid
1vyu	Beta3 subunit of voltage-gated ca2+-channel
1vyv	Beta4 subunit of ca2+ channel
1w1f	Sh3 domain of human lyn tyrosine kinase
1w6x	Sh3 domain of p40phox, component of the nadph oxidase
1w70	Sh3 domain of p40phox complexed with c-terminal polyproline region of p47phox
1wa7	Sh3 domain of human lyn tyrosine kinase in complex with a herpesviral ligand
1wdx	Yeast bbc1 sh3 domain, triclinic crystal form
1wfw	Solution structure of sh3 domain of mouse kalirin-9a protein
1wi7	Solution structure of the sh3 domain of sh3-domain kinase binding protein 1
1wie	Solution structure of the first sh3 domain of kiaa0318 protein
1wlp	Solution structure of the p22phox-p47phox complex
1wx6	Solution structure of the sh3 domain of the human cytoplasmic protein nck2
1wxb	Solution structure of the sh3 domain from human epidermal growth factor receptor pathway substrate 8-like protein
1wxt	Solution structure of the sh3 domain of human hypothetical protein flj21522
1wxu	Solution structure of the sh3 domain of mouse peroxisomal biogenesis factor 13
1wyx	The crystal structure of the p130cas sh3 domain at 1.1 a resolution
1x27	Crystal structure of lck sh2-sh3 with sh2 binding site of p130cas
1x2k	Solution structure of the sh3 domain of human osteoclast stimulating factor 1 (ostf1)
1x2p	Solution structure of the sh3 domain of the protein arginine n-methyltransferase 2
1x2q	Solution structure of the sh3 domain of the signal transducing adaptor molecule 2
1x43	Solution structure of the sh3 domain of endophilin b1 (sh3g1b1)
1x69	Solution structures of the sh3 domain of human src substrate cortactin
1x6b	Solution structures of the sh3 domain of human rho guanine exchange factor (gef) 16
1x6g	Solution structures of the sh3 domain of human megakaryocyte-associated tyrosine-protein kinase.
1y0m	Crystal structure of of the sh3 domain of phospholipase c gamma-1
1y57	Structure of unphosphorylated c-src in complex with an inhibitor
1ycs	P53-53bp2 complex
1yn8	Sh3 domain of yeast nbp2
1ynz	Sh3 domain of yeast pin3
1yp5	Yeast myo5 sh3 domain, tetragonal crystal form
1ywo	Phospholipase cgamma1 sh3 in complex with a slp-76 motif
1ywp	Phospholipase cgamma1 sh3
1z9q	Solution structure of sh3 domain of p40phox
1z9z	Crystal structure of yeast sla1 sh3 domain 3
1zbj	Inferential structure determination of the fyn sh3 domain using noesy data from a 15n,h2 enriched protein
1zlm	Crystal structure of the sh3 domain of human osteoclast stimulating factor
1zsg	Beta pix-sh3 complexed with an atypical peptide from alpha- pak
1zuk	Yeast bbc1 sh3 domain complexed with a peptide from las17
1zuu	Crystal structure of the yeast bzz1 first sh3 domain at 0.97-a resolution
1zuy	High-resolution structure of yeast myo5 sh3 domain
1zx6	High-resolution crystal structure of yeast pin3 sh3 domain
2a08	Structure of the yeast yhh6 sh3 domain
2a28	Atomic-resolution crystal structure of the second sh3 domain of yeast bzz1 determined from a pseudomerohedrally twinned crystal
2a36	Solution structure of the n-terminal sh3 domain of drk
2a37	Solution structure of the t22g mutant of n-terminal sh3 domain of drk (drkn sh3 domain)
2abl	Sh3-sh2 domain fragment of human bcr-abl tyrosine kinase
2ak5	Beta pix-sh3 complexed with a cbl-b peptide
2azs	Nmr structure of the n-terminal sh3 domain of drk (calculated without noe restraints)
2azv	Solution structure of the t22g mutant of n-terminal sh3 domain of drk (calculated without noes)
2b86	Solution structure of the first src homology 3 domain of nck2
2btt	Nmr structure of myo3-sh3 domain from myosin-type i from s. cerevisiae
2bz8	N-terminal sh3 domain of cin85 bound to cbl-b peptide
2bzx	Atomic model of crkl-sh3c monomer
2bzy	Dimeric of crkl-sh3c domain
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
2cdt	Alpha-spectrin sh3 domain a56s mutant
2cre	Solution structure of rsgi ruh-036, an sh3 domain from human cdna
2csi	Solution structure of the third sh3 domain of human rim- binding protein 2
2csq	Solution structure of the second sh3 domain of human rim- binding protein 2
2ct3	Solution structure of the sh3 domain of the vinexin protein
2ct4	Solution strutcure of the sh3 domain of the cdc42- interacting protein 4
2cub	Solution structure of the sh3 domain of the human cytoplasmic protein nck1
2cuc	Solution structure of the sh3 domain of the mouse hypothetical protein sh3rf2
2cud	Solution structure of the sh3 domain of the human src-like adopter protein (slap)
2d0n	Crystal structure of the c-terminal sh3 domain of the adaptor protein gads in complex with slp-76 motif peptide reveals a unique sh3-sh3 interaction
2d1x	The crystal structure of the cortactin-sh3 domain and amap1- peptide complex
2d8h	Solution structure of the sh3 domain of hypothetical protein sh3yl1
2d8j	Solution structure of the sh3 domain of fyn-related kinase
2da9	Solution structure of the third sh3 domain of sh3-domain kinase binding protein 1 (regulator of ubiquitous kinase, ruk)
2dbk	Solution structures of the sh3 domain of human crk-like protein
2dbm	Solution structures of the sh3 domain of human sh3- containing grb2-like protein 2
2de0	Crystal structure of human alpha 1,6-fucosyltransferase, fut8
2df6	Crystal structure of the sh3 domain of betapix in complex with a high affinity peptide from pak2
2dil	Solution structure of the sh3 domain of the human proline- serine-threonine phosphatase-interacting protein 1
2djq	The solution structure of the first sh3 domain of mouse sh3 domain containing ring finger 2
2dl3	Solution structure of the first sh3 domain of human sorbin and sh3 domain-containing protein 1
2dl4	Solution structure of the first sh3 domain of stac protein
2dl5	Solution structure of the first sh3 domain of human kiaa0769 protein
2dl7	Solution structure of the second sh3 domain of human kiaa0769 protein
2dl8	Solution structure of the sh3 domain of human slit-robo rho gtpase-activating protein 2
2dlm	Solution structure of the first sh3 domain of human vinexin
2dlp	Solution structure of the sh3 domain of human kiaa1783 protein
2dm1	Solution structure of the second sh3 domain of human protein vav-2
2dmo	Refined solution structure of the 1st sh3 domain from human neutrophil cytosol factor 2 (ncf-2)
2dnu	Solution structure of rsgi ruh-061, a sh3 domain from human
2drk	Acanthamoeba myosin i sh3 domain bound to acan125
2drm	Acanthamoeba myosin i sh3 domain bound to acan125
2dvj	Phosphorylated crk-ii
2dx1	Crystal structure of rhogef protein asef
2dyb	The crystal structure of human p40(phox)
2e5k	Solution structure of sh3 domain in suppressor of t-cell receptor signaling 1
2ebp	Solution structure of the sh3 domain from human sam and sh3 domain containing protein 1
2ecz	Solution structure of the sh3 domain of sorbin and sh3 domain-containing protein 1
2ed0	Solution structure of the sh3 domain of abl interactor 2 (abelson interactor 2)
2ed1	Solution structure of the sh3 domain of 130 kda phosphatidylinositol 4,5-biphosphate-dependent arf1 gtpase- activating protein
2ega	Solution structure of the first sh3 domain from human kiaa0418 protein
2egc	Solution structure of the fifth sh3 domain from human kiaa0418 protein
2ege	Solution structure of the third sh3 domain from human kiaa1666 protein
2ekh	Solution structures of the sh3 domain of human kiaa0418
2enm	Solution structure of the sh3 domain from mouse sorting nexin-9
2epd	Solution structure of sh3 domain in rho-gtpase-activating protein 4
2eqi	Solution structure of the sh3 domain from phospholipase c, gamma 2
2esw	Atomic structure of the n-terminal sh3 domain of mouse beta pix,p21-activated kinase (pak)-interacting exchange factor
2ew3	Solution structure of the sh3 domain of human sh3gl3
2eyw	N-terminal sh3 domain of ct10-regulated kinase
2eyx	C-terminal sh3 domain of ct10-regulated kinase
2eyy	Ct10-regulated kinase isoform i
2eyz	Ct10-regulated kinase isoform ii
2f2v	Alpha-spectrin sh3 domain a56g mutant
2f2w	Alpha-spectrin sh3 domain r21a mutant
2f2x	Alpha-spectrin sh3 domain r21g mutant
2fei	Solution structure of the second sh3 domain of human cms protein
2fo0	Organization of the sh3-sh2 unit in active and inactive forms of the c-abl tyrosine kinase
2fpd	Sad structure determination: crystal structure of the intrinsic dimerization sh3 domain of the ib1 scaffold protein
2fpe	Conserved dimerization of the ib1 src-homology 3 domain
2fpf	Crystal structure of the ib1 sh3 dimer at low resolution
2frw	Solution structure of the second sh3 domain of human adaptor protein nck2
2fry	Solution structure of the third sh3 domain of human nck2 adaptor protein
2g6f	Crystal structure of the sh3 domain of betapix in complex with a high affinity peptide from pak2
2gbq	Solution nmr structure of the grb2 n-terminal sh3 domain complexed with a ten-residue peptide derived from sos direct refinement against noes, j-couplings, and 1h and 13c chemical shifts, 15 structures
2ggr	Solution structure of the c-terminal sh3 domain of c-crkii
2gnc	Crystal structure of srgap1 sh3 domain in the slit-robo signaling pathway
2gqi	Solution structure of the sh3 domain of human ras gtpase- activating protein 1
2gtj	Reduced form of adap hsh3-n-domain
2gto	Oxidized form of adap hsh3-n
2h8h	Src kinase in complex with a quinazoline inhibitor
2hck	Src family kinase hck-quercetin complex
2hda	Yes sh3 domain
2hsp	Solution structure of the sh3 domain of phospholipase cgamma
2i0n	Structure of dictyostelium discoideum myosin vii sh3 domain with adjacent proline rich region
2iim	Sh3 domain of human lck
2j05	Crystal structure of the rasgap sh3 domain at 1.5 angstrom resolution
2j06	Crystal structure of the rasgap sh3 domain at 1.8 angstrom resolution
2j6f	N-terminal sh3 domain of cms (cd2ap human homolog) bound to cbl-b peptide
2j6k	N-terminal sh3 domain of cms (cd2ap human homolog)
2j6o	Atypical polyproline recognition by the cms n-terminal sh3 domain. cms:cd2 heterotrimer
2j7i	Atypical polyproline recognition by the cms n-terminal sh3 domain. cms:cd2 heterodimer
2jm8	R21a spc-sh3 free
2jm9	R21a spc-sh3 bound
2jma	R21a spc-sh3:p41 complex
2jmc	Chimer between spc-sh3 and p41
2js0	Solution structure of second sh3 domain of adaptor nck
2js2	Solution structure of first sh3 domain of adaptor nck
2jt4	Solution structure of the sla1 sh3-3-ubiquitin complex
2jte	Third sh3 domain of cd2ap
2jw4	Nmr solution structure of the n-terminal sh3 domain of human nckalpha
2jxb	Structure of cd3epsilon-nck2 first sh3 domain complex
2k2m	Structural basis of pxxdy motif recognition in sh3 binding
2k3b	Seeing the invisible: structures of excited protein states by relaxation dispersion nmr
2k6d	Cin85 sh3-c domain in complex with ubiquitin
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.
2k9g	Solution structure of the third sh3 domain of the cin85 adapter protein
2kbt	Attachment of an nmr-invisible solubility enhancement tag (inset) using a sortase-mediated protein ligation method
2nuz	Crystal structure of alpha spectrin sh3 domain measured at room temperature
2nwm	Solution structure of the first sh3 domain of human vinexin and its interaction with the peptides from vinculin
2o2o	Solution structure of domain b from human cin85 protein
2o2w	Extending powder diffraction to proteins: structure solution of the second sh3 domain from ponsin
2o31	Crystal structure of the second sh3 domain from ponsin
2o88	Crystal structure of the n114a mutant of abl-sh3 domain complexed with a designed high-affinity peptide ligand: implications for sh3-ligand interactions
2o9s	The second sh3 domain from ponsin
2o9v	The second sh3 domain from ponsin in complex with the paxillin proline rich region
2oaw	Structure of shh variant of "bergerac" chimera of spectrin sh3
2oi3	Nmr structure analysis of the hematopoetic cell kinase sh3 domain complexed with an artificial high affinity ligand (pd1)
2oj2	Nmr structure analysis of the hematopoetic cell kinase sh3 domain complexed with an artificial high affinity ligand (pd1)
2p4r	Structural basis for a novel interaction between aip4 and beta-pix
2pni	Solution structure and ligand-binding site of the sh3 domain of the p85alpha subunit of phosphatidylinositol 3- kinase
2pqh	Structure of sh3 chimera with a type ii ligand linked to the chain c-terminal
2ptk	Chicken src tyrosine kinase
2pz1	Crystal structure of auto-inhibited asef
2rf0	Crystal structure of human mixed lineage kinase map3k10 sh3 domain
2rmo	Solution structure of alpha-spectrin_sh3-bergerac from chicken
2rn8	Nmr structure note: murine itk sh3 domain
2rna	Itk sh3 average minimized
2rol	Structural basis of pxxdy motif recognition in sh3 binding
2rot	Structure of chimeric variant of sh3 domain- shh
2rpn	A crucial role for high intrinsic specificity in the function of yeast sh3 domains
2sem	Sem5 sh3 domain complexed with peptoid inhibitor
2src	Crystal structure of human tyrosine-protein kinase c-src, in complex with amp-pnp
2v1q	Atomic-resolution structure of the yeast sla1 sh3 domain 3
2v1r	Yeast pex13 sh3 domain complexed with a peptide from pex14 at 2.1 a resolution
2vge	Crystal structure of the c-terminal region of human iaspp
2vkn	Yeast sho1 sh3 domain complexed with a peptide from pbs2
2vvk	Grb2 sh3c (1)
2vwf	Grb2 sh3c (2)
2w0z	Grb2 sh3c (3)
2w10	Mona sh3c in complex
2ysq	Solution structure of the sh3 domain from rho guanine nucleotide exchange factor 9
2yt6	Solution structure of the sh3_1 domain of yamaguchi sarcoma viral (v-yes) oncogene homolog 1
2yun	Solution structure of the sh3 domain of human nostrin
2yuo	Solution structure of the sh3 domain of mouse run and tbc1 domain containing 3
2yup	Solution structure of the second sh3 domain of human vinexin
2yuq	Solution structure of the sh3 domain of human tyrosine- protein kinase itk/tsk
3c0c	X-ray crystal structure of the rat endophilin a2 sh3 domain
3cqt	N53i v55l mutant of fyn sh3 domain
3eg0	Crystal structure of the n114t mutant of abl-sh3 domain
3eg1	Crystal structure of the n114q mutant of abl-sh3 domain complexed with a designed high-affinity peptide ligand: implications for sh3-ligand interactions
3eg2	Crystal structure of the n114q mutant of abl-sh3 domain
3eg3	Crystal structure of the n114a mutant of abl-sh3 domain
3egu	Crystal structure of the n114a mutant of abl-sh3 domain
3ehq	Crystal structure of human osteoclast stimulating factor
3ehr	Crystal structure of human osteoclast stimulating factor
3fj5	Crystal structure of the c-src-sh3 domain
3gbq	Solution nmr structure of the grb2 n-terminal sh3 domain complexed with a ten-residue peptide derived from sos direct refinement against noes, j-couplings, and 1h and 13c chemical shifts, minimized average structure
3haj	Crystal structure of human pacsin2 f-bar domain (p212121 lattice)
3i35	Human sh3 domain of protein lasp1
3iql	Crystal structure of the rat endophilin-a1 sh3 domain
3kfv	Crystal structure of the sh3-kinase fragment of tight junction protein 3 (tjp3) in apo-form
3sem	Sem5 sh3 domain complexed with peptoid inhibitor
4gbq	Solution nmr structure of the grb2 n-terminal sh3 domain complexed with a ten-residue peptide derived from sos direct refinement against noes, j-couplings, and 1h and 13c chemical shifts, 15 structures
4hck	Human hck sh3 domain, nmr, 25 structures
5hck	Human hck sh3 domain, nmr, minimized average structure

Links (links to other resources describing this domain)

• BLOCKS: SH3
• PFAM: SH3
• INTERPRO: IPR001452
• PROSITE: SH3