IlGF

Insulin / insulin-like growth factor / relaxin family.

• SMART accession number: SM00078
• Description: Family of proteins including insulin, relaxin, and IGFs. Insulin decreases blood glucose concentration.
• Interpro abstract (IPR016179):

  The insulin family of proteins groups together several evolutionarily related active peptides [(PUBMED:6107857)]: these include insulin [(PUBMED:6243748), (PUBMED:503234)], relaxin [(PUBMED:10601981), (PUBMED:8735594)], insect prothoracicotropic hormone (bombyxin) [(PUBMED:8683595)], insulin-like growth factors (IGF1 and IGF2) [(PUBMED:2036417), (PUBMED:1319992)], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [(PUBMED:2036417), (PUBMED:1319992), (PUBMED:9141131)]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain.

  Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver [(PUBMED:6243748)]. Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth [(PUBMED:6243748)].

  Insulin is synthesised as a prepropeptide from which an endoplasmic reticulum-targeting sequence is cleaved to yield proinsulin. The sequence of prosinsulin contains 2 well-conserved regions (designated A and B), separated by an intervening connecting region (C), which is variable between species [(PUBMED:503234)]. The connecting region is cleaved, liberating the active protein, which contains the A and B chains, held together by 2 disulphide bonds [(PUBMED:503234)].

  This entry represents a disulphide-rich alpha-helical domain found in insulin [(PUBMED:12595704)], as well as in related proteins, such as insulin-like growth factor [(PUBMED:15642270)], relaxin [(PUBMED:1656049)] and bombyxin [(PUBMED:7473749)].

• GO component: extracellular region (GO:0005576)
• GO function: hormone activity (GO:0005179)

There are 753 IlGF domains in 753 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

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

• Schwabe C, Bullesbach EE
• Relaxin: structures, functions, promises, and nonevolution.
• FASEB J. 1994; 8: 1152-60

During the last two decades synthetic chemistry and molecular biology have transformed the little-known parturition-mediating factor relaxin into a chemically defined entity. Relaxin is a disulfide bond analog of insulin that shows no cross-reactivity to the insulin receptors, causes widening of the birth canal in most mammals, and has additional or different functions in various species. The receptor interaction site in relaxin has been located quite precisely in the midregion of the B chain helix and is now known to involve two arginine residues that project from the alpha helix in an n, n + 4 configuration. The A chain of relaxin which appears to be uninvolved in receptor binding, is nonetheless essential. In fact, a major structural determinant in relaxin and insulin responsible for achieving either an insulin-like or a relaxin-like conformation is located in the penultimate position in the intrachain loop of the A chains.

• Murray-Rust J, McLeod AN, Blundell TL, Wood SP
• Structure and evolution of insulins: implications for receptor binding.
• Bioessays. 1992; 14: 325-31

Insulin is a member of a family of hormones, growth factors and neuropeptides which are found in both vertebrates and invertebrates. A common 'insulin fold' is probably adopted by all family members. Although the specificities of receptor binding are different, there is a possibility of co-evolution of polypeptides and their receptors.

• Blundell TL, Humbel RE
• Hormone families: pancreatic hormones and homologous growth factors.
• Nature. 1980; 287: 781-7

The growing realization that biologically active polypeptides can be grouped in families, the members of which show structural and functional relatedness, is illustrated by the four families which are represented in the pancreas by the hormones insulin, glucagon, somatostatin and pancreatic polypeptide.

• Bedarkar S, Turnell WG, Blundell TL, Schwabe C
• Relaxin has conformational homology with insulin.
• Nature. 1977; 270: 449-51

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

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

Protein	Disease
Insulin A chain (P01308) (SMART)	OMIM:176730: Diabetes mellitus, rare form ; MODY, one form ; Hyperproinsulinemia, familial

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
10.75	map05215	Prostate cancer
10.75	map04150	mTOR signaling pathway
10.75	map04914	Progesterone-mediated oocyte maturation
6.45	map04950	Maturity onset diabetes of the young
6.45	map05050	Dentatorubropallidoluysian atrophy (DRPLA)
6.45	map04140	Regulation of autophagy
6.45	map04940	Type I diabetes mellitus
6.45	map04910	Insulin signaling pathway
6.45	map04810	Regulation of actin cytoskeleton
6.45	map04930	Type II diabetes mellitus
4.30	map04510	Focal adhesion
4.30	map05214	Glioma
4.30	map04730	Long-term depression
4.30	map04115	p53 signaling pathway
4.30	map05218	Melanoma
1.08	map00380	Tryptophan 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 IlGF domain which could be assigned to a KEGG orthologous group, and not all proteins containing IlGF 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 IlGF domains in PDB

PDB code	Title
1a7f	Insulin mutant b16 glu, b24 gly, des-b30, nmr, 20 structures
1ai0	R6 human insulin hexamer (non-symmetric), nmr, 10 structures
1aiy	R6 human insulin hexamer (symmetric), nmr, 10 structures
1aph	Conformational changes in cubic insulin crystals in the ph range 7-11
1b17	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 5.00 coordinates)
1b18	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 5.53 coordinates)
1b19	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 5.80 coordinates)
1b2a	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 6.00 coordinates)
1b2b	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 6.16 coordinates)
1b2c	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 6.26 coordinates)
1b2d	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 6.35 coordinates)
1b2e	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 6.50 coordinates)
1b2f	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 6.98 coordinates)
1b2g	Ph affects glu b13 switching and sulfate binding in cubic insulin crystals (ph 9.00 coordinates)
1b9e	Human insulin mutant serb9glu
1b9g	Insulin-like-growth-factor-1
1ben	Insulin complexed with 4-hydroxybenzamide
1bom	Three-dimensional structure of bombyxin-ii, an insulin- related brain-secretory peptide of the silkmoth bombyx mori: comparison with insulin and relaxin
1bon	Three-dimensional structure of bombyxin-ii, an insulin- related brain-secretory peptide of the silkmoth bombyx mori: comparison with insulin and relaxin
1bph	Conformational changes in cubic insulin crystals in the ph range 7-11
1bqt	Three-dimensional structure of human insulin-like growth factor-i (igf-i) determined by 1h-nmr and distance geometry, 6 structures
1bzv	[d-alab26]-des(b27-b30)-insulin-b26-amide a superpotent single-replacement insulin analogue, nmr, minimized average structure
1cph	Conformational changes in cubic insulin crystals in the ph range 7-11
1dei	Desheptapeptide (b24-b30) insulin
1dph	Conformational changes in cubic insulin crystals in the ph range 7-11
1efe	An active mini-proinsulin, m2pi
1ev3	Structure of the rhombohedral form of the m-cresol/insulin r6 hexamer
1ev6	Structure of the monoclinic form of the m-cresol/insulin r6 hexamer
1evr	The structure of the resorcinol/insulin r6 hexamer
1fu2	First protein structure determined from x-ray powder diffraction data
1fub	First protein structure determined from x-ray powder diffraction data
1g7a	1.2 a structure of t3r3 human insulin at 100 k
1g7b	1.3 a structure of t3r3 human insulin at 100 k
1guj	Insulin at ph 2: structural analysis of the conditions promoting insulin fibre formation.
1gzr	Human insulin-like growth factor; esrf data
1gzy	Human insulin-like growth factor; in-house data
1gzz	Human insulin-like growth factor; hamburg data
1h02	Human insulin-like growth factor; srs daresbury data
1h59	Complex of igfbp-5 with igf-i
1hiq	Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus
1his	Structure and dynamics of des-pentapeptide-insulin in solution: the molten-globule hypothesis
1hit	Receptor binding redefined by a structural switch in a mutant human insulin
1hls	Nmr structure of the human insulin-his(b16)
1ho0	New b-chain mutant of bovine insulin
1htv	Crystal structure of destripeptide (b28-b30) insulin
1hui	Insulin mutant (b1, b10, b16, b27)glu, des-b30, nmr, 25 structures
1igl	Solution structure of human insulin-like growth factor ii relationship to receptor and binding protein interactions
1imx	1.8 angstrom crystal structure of igf-1
1iog	Insulin mutant a3 gly,(b1, b10, b16, b27)glu, des-b30, nmr, structures
1ioh	Insulin mutant a8 his,(b1, b10, b16, b27)glu, des-b30, nmr, structures
1iza	Role of b13 glu in insulin assembly: the hexamer structure of recombinant mutant (b13 glu-> gln) insulin
1izb	Role of b13 glu in insulin assembly: the hexamer structure of recombinant mutant (b13 glu-> gln) insulin
1j73	Crystal structure of an unstable insulin analog with native activity.
1jca	Non-standard design of unstable insulin analogues with enhanced activity
1jco	Solution structure of the monomeric [thr(b27)->pro,pro(b28)- >thr] insulin mutant (pt insulin)
1k3m	Nmr structure of human insulin mutant ile-a2-ala, his-b10- asp, pro-b28-lys, lys-b29-pro, 15 structures
1kmf	Nmr structure of human insulin mutant ile-a2-allo-ile, his- b10-asp, pro-b28-lys, lys-b29-pro, 15 structures
1lkq	Nmr structure of human insulin mutant ile-a2-gly, val-a3- gly, his-b10-asp, pro-b28-lys, lys-b29-pro, 20 structures
1lph	Lys(b28)pro(b29)-human insulin
1m5a	Crystal structure of 2-co(2+)-insulin at 1.2a resolution
1mhi	Three-dimensional solution structure of an insulin dimer. a study of the b9(asp) mutant of human insulin using nuclear magnetic resonance distance geometry and restrained molecular dynamics
1mhj	Solution structure of the superactive monomeric des- [phe(b25)] human insulin mutant. elucidation of the structural basis for the monomerization of the des- [phe(b25)] insulin and the dimerization of native insulin
1mpj	X-ray crystallographic studies on hexameric insulins in the presence of helix-stabilizing agents, thiocyanate, methylparaben and phenol
1mso	T6 human insulin at 1.0 a resolution
1os3	Dehydrated t6 human insulin at 100 k
1os4	Dehydrated t6 human insulin at 295 k
1pid	Bovine despentapeptide insulin
1pmx	Insulin-like growth factor-i bound to a phage-derived peptide
1q4v	Crystal structure of allo-ilea2-insulin, an inactive chiral analogue: implications for the mechanism of receptor
1qiy	Human insulin hexamers with chain b his mutated to tyr complexed with phenol
1qiz	Human insulin hexamers with chain b his mutated to tyr complexed with resorcinol
1qj0	Human insulin hexamers with chain b his mutated to tyr
1rwe	Enhancing the activity of insulin at receptor edge: crystal structure and photo-cross-linking of a8 analogues
1sdb	Porcine desb1-2 despentapeptide(b26-b30) insulin
1sf1	Nmr structure of human insulin under amyloidogenic condition, 15 structures
1sjt	Mini-proinsulin, two chain insulin analog mutant: des b30, his(b 10)asp, pro(b 28)asp, nmr, 20 structures
1sju	Mini-proinsulin, single chain insulin analog mutant: des b30, his(b 10)asp, pro(b 28)asp and peptide bond between lys b 29 and gly a 1, nmr, 20 structures
1t1k	Nmr structure of human insulin mutant his-b10-asp, val-b12- ala, pro-b28-lys, lys-b29-pro, 15 structures
1t1p	Nmr structure of human insulin mutant his-b10-asp, val-b12- thr, pro-b28-lys, lys-b29-pro, 15 structures
1t1q	Nmr structure of human insulin mutant his-b10-asp, val-b12- aba, pro-b28-lys, lys-b29-pro, 15 structures
1tgr	Crystal structure of mini-igf-1(2)
1trz	Crystallographic evidence for dual coordination around zinc in the t3r3 human insulin hexamer
1tyl	The structure of a complex of hexameric insulin and 4'- hydroxyacetanilide
1tym	The structure of a complex of hexameric insulin and 4'- hydroxyacetanilide
1uz9	Crystallographic and solution studies of n-lithocholyl insulin: a new generation of prolonged-acting insulins.
1vkt	Human insulin two disulfide model, nmr, 10 structures
1w8p	Structural properties of the b25tyr-nme-b26phe insulin mutant.
1wav	Crystal structure of form b monoclinic crystal of insulin
1wqj	Structural basis for the regulation of insulin-like growth factors (igfs) by igf binding proteins (igfbps)
1xda	Structure of insulin
1xgl	Human insulin disulfide isomer, nmr, 10 structures
1xw7	Diabetes-associated mutations in human insulin: crystal structure and photo-cross-linking studies of a-chain variant insulin wakayama
1zeg	Structure of b28 asp insulin in complex with phenol
1zeh	Structure of insulin
1zei	Cross-linked b28 asp insulin
1zni	Insulin
1znj	Insulin, monoclinic crystal form
2a3g	The structure of t6 bovine insulin
2aiy	R6 human insulin hexamer (symmetric), nmr, 20 structures
2bn1	Insulin after a high dose x-ray burn
2bn3	Insulin before a high dose x-ray burn
2c8q	Insuline(1sec) and uv laser excited fluorescence
2c8r	Insuline(60sec) and uv laser excited fluorescence
2ceu	Despentapeptide insulin in acetic acid (ph 2)
2dsp	Structural basis for the inhibition of insulin-like growth factors by igf binding proteins
2dsq	Structural basis for the inhibition of insulin-like growth factors by igf binding proteins
2dsr	Structural basis for the inhibition of insulin-like growth factors by igf binding proteins
2efa	Neutron crystal structure of cubic insulin at pd6.6
2g4m	Insulin collected at 2.0 a wavelength
2g54	Crystal structure of zn-bound human insulin-degrading enzyme in complex with insulin b chain
2g56	Crystal structure of human insulin-degrading enzyme in complex with insulin b chain
2gf1	Solution structure of human insulin-like growth factor 1: a nuclear magnetic resonance and restrained molecular dynamics study
2h67	Nmr structure of human insulin mutant his-b5-ala, his-b10- asp pro-b28-lys, lys-b29-pro, 20 structures
2hh4	Nmr structure of human insulin mutant gly-b8-d-ser, his-b10- asp pro-b28-lys, lys-b29-pro, 20 structures
2hho	Nmr structure of human insulin mutant gly-b8-ser, his-b10- asp pro-b28-lys, lys-b29-pro, 20 structures
2hiu	Nmr structure of human insulin in 20% acetic acid, zinc- free, 10 structures
2ins	The structure of des-phe b1 bovine insulin
2jmn	Nmr structure of human insulin mutant his-b10-asp, pro-b28- lys, lys-b29-pro, 20 structures
2jum	Thra3-dkp-insulin
2juu	Allo-thra3 dkp-insulin
2juv	Abaa3-dkp-insulin
2jv1	Nmr structure of human insulin monomer in 35% cd3cn zinc free, 50 structures
2jzq	Design of an active ultra-stable single-chain insulin analog 20 structures
2k91	Enhancing the activity of insulin by stereospecific unfolding
2k9r	Enhancing the activity of insulin by stereospecific unfolding
2kji	A divergent ins protein in c. elegans structurally resemble insulin and activates the human insulin receptor
2oly	Structure of human insulin in presence of urea at ph 7.0
2olz	Structure of human insulin in presence of thiocyanate at ph 7.0
2om0	Structure of human insulin in presence of urea at ph 6.5
2om1	Structure of human insulin in presence of thiocyanate at ph 6.5
2omg	Structure of human insulin cocrystallized with protamine and urea
2omh	Structure of human insulin cocrystallized with arg-12 peptide in presence of urea
2omi	Structure of human insulin cocrystallized with protamine
2qiu	Structure of human arg-insulin
2r34	Crystal structure of mn human arg-insulin
2r35	Crystal structure of rb human arg-insulin
2r36	Crystal structure of ni human arg-insulin
2rn5	Humal insulin mutant b31lys-b32arg
2tci	X-ray crystallographic studies on hexameric insulins in the presence of helix-stabilizing agents, thiocyanate, methylparaben and phenol
2v5p	Complex structure of human igf2r domains 11-13 bound to igf-ii
2vjz	Crystal structure form ultalente insulin microcrystals
2vk0	Crystal structure form ultalente insulin microcrystals
2wby	Crystal structure of human insulin-degrading enzyme in complex with insulin
2wc0	Crystal structure of human insulin degrading enzyme in complex with iodinated insulin
2zp6	Crystal structure of bovine insulin (hexameric form)
2zpp	Neutron crystal structure of cubic insulin at pd9
3aiy	R6 human insulin hexamer (symmetric), nmr, refined average structure
3brr	Crystal structure of insulin in complex with sulfatide
3bxq	The structure of a mutant insulin uncouples receptor binding from protein allostery. an electrostatic block to the tr transition
3e4z	Crystal structure of human insulin degrading enzyme in complex with insulin-like growth factor ii
3e7y	Structure of human insulin
3e7z	Structure of human insulin
3exx	Structure of the t6 human insulin derivative with nickel at 1.35 a resolution
3fhp	A neutron crystallographic analysis of a porcine 2zn insulin at 2.0 a resolution
3fq9	Design of an insulin analog with enhanced receptor-binding selectivity. rationale, structure, and therapeutic implications
3gf1	Solution structure of human insulin-like growth factor 1: a nuclear magnetic resonance and restrained molecular dynamics study
3gky	The structural basis of an er stress-associated bottleneck in a protein folding landscape
3ins	Structure of insulin. results of joint neutron and x-ray refinement
3lri	Solution structure and backbone dynamics of long-[arg(3) ]insulin-like growth factor-i
3mth	X-ray crystallographic studies on hexameric insulins in the presence of helix-stabilizing agents, thiocyanate, methylparaben and phenol
4aiy	R6 human insulin hexamer (symmetric), nmr, 'green' substate, average structure
4ins	The structure of 2zn pig insulin crystals at 1.5 angstroms resolution
5aiy	R6 human insulin hexamer (symmetric), nmr, 'red' substate, average structure
6ins	X-ray analysis of the single chain /b29-a1$ peptide-linked insulin molecule. a completely inactive analogue
7ins	Structure of porcine insulin cocrystallized with clupeine z
9ins	Monovalent cation binding in cubic insulin crystals

Links (links to other resources describing this domain)

• BLOCKS: INSULIN
• PFAM: ins
• INTERPRO: IPR016179
• PROSITE: IlGF_DOMAIN