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2dtg

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2dtg, resolution 3.80Å ()
Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Insulin receptor (IR) ectodomain in complex with fab's

Publication Abstract from PubMed

The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.

Structure of the insulin receptor ectodomain reveals a folded-over conformation., McKern NM, Lawrence MC, Streltsov VA, Lou MZ, Adams TE, Lovrecz GO, Elleman TC, Richards KM, Bentley JD, Pilling PA, Hoyne PA, Cartledge KA, Pham TM, Lewis JL, Sankovich SE, Stoichevska V, Da Silva E, Robinson CP, Frenkel MJ, Sparrow LG, Fernley RT, Epa VC, Ward CW, Nature. 2006 Sep 14;443(7108):218-21. Epub 2006 Sep 6. PMID:16957736

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[INSR_HUMAN] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:262190]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.[1][2][3][4][5][6] Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:246200]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:125853]; also known as diabetes mellitus type 2.[24][25][26] Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:609968]. Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.[27] Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor.

Function

[INSR_HUMAN] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.[28][29][30][31][32][33][34][35]

About this Structure

2dtg is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA.

See Also

Reference

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  1. Kadowaki T, Kadowaki H, Accili D, Taylor SI. Substitution of lysine for asparagine at position 15 in the alpha-subunit of the human insulin receptor. A mutation that impairs transport of receptors to the cell surface and decreases the affinity of insulin binding. J Biol Chem. 1990 Nov 5;265(31):19143-50. PMID:2121734
  2. Kadowaki T, Kadowaki H, Rechler MM, Serrano-Rios M, Roth J, Gorden P, Taylor SI. Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest. 1990 Jul;86(1):254-64. PMID:2365819 doi:http://dx.doi.org/10.1172/JCI114693
  3. Krook A, Kumar S, Laing I, Boulton AJ, Wass JA, O'Rahilly S. Molecular scanning of the insulin receptor gene in syndromes of insulin resistance. Diabetes. 1994 Mar;43(3):357-68. PMID:8314008
  4. Longo N, Wang Y, Pasquali M. Progressive decline in insulin levels in Rabson-Mendenhall syndrome. J Clin Endocrinol Metab. 1999 Aug;84(8):2623-9. PMID:10443650
  5. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002 Jun 1;11(12):1465-75. PMID:12023989
  6. Tuthill A, Semple RK, Day R, Soos MA, Sweeney E, Seymour PJ, Didi M, O'rahilly S. Functional characterization of a novel insulin receptor mutation contributing to Rabson-Mendenhall syndrome. Clin Endocrinol (Oxf). 2007 Jan;66(1):21-6. PMID:17201797 doi:CEN2678
  7. Kadowaki T, Kadowaki H, Rechler MM, Serrano-Rios M, Roth J, Gorden P, Taylor SI. Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest. 1990 Jul;86(1):254-64. PMID:2365819 doi:http://dx.doi.org/10.1172/JCI114693
  8. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002 Jun 1;11(12):1465-75. PMID:12023989
  9. Kadowaki T, Bevins CL, Cama A, Ojamaa K, Marcus-Samuels B, Kadowaki H, Beitz L, McKeon C, Taylor SI. Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. Science. 1988 May 6;240(4853):787-90. PMID:2834824
  10. Klinkhamer MP, Groen NA, van der Zon GC, Lindhout D, Sandkuyl LA, Krans HM, Moller W, Maassen JA. A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance. EMBO J. 1989 Sep;8(9):2503-7. PMID:2479553
  11. Barbetti F, Gejman PV, Taylor SI, Raben N, Cama A, Bonora E, Pizzo P, Moghetti P, Muggeo M, Roth J. Detection of mutations in insulin receptor gene by denaturing gradient gel electrophoresis. Diabetes. 1992 Apr;41(4):408-15. PMID:1607067
  12. van der Vorm ER, van der Zon GC, Moller W, Krans HM, Lindhout D, Maassen JA. An Arg for Gly substitution at position 31 in the insulin receptor, linked to insulin resistance, inhibits receptor processing and transport. J Biol Chem. 1992 Jan 5;267(1):66-71. PMID:1730625
  13. al-Gazali LI, Khalil M, Devadas K. A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. J Med Genet. 1993 Jun;30(6):470-5. PMID:8326490
  14. Longo N, Langley SD, Griffin LD, Elsas LJ. Activation of glucose transport by a natural mutation in the human insulin receptor. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):60-4. PMID:8419945
  15. van der Vorm ER, Kuipers A, Kielkopf-Renner S, Krans HM, Moller W, Maassen JA. A mutation in the insulin receptor that impairs proreceptor processing but not insulin binding. J Biol Chem. 1994 May 13;269(19):14297-302. PMID:8188715
  16. Hone J, Accili D, al-Gazali LI, Lestringant G, Orban T, Taylor SI. Homozygosity for a new mutation (Ile119-->Met) in the insulin receptor gene in five sibs with familial insulin resistance. J Med Genet. 1994 Sep;31(9):715-6. PMID:7815442
  17. Longo N, Langley SD, Griffin LD, Elsas LJ. Two mutations in the insulin receptor gene of a patient with leprechaunism: application to prenatal diagnosis. J Clin Endocrinol Metab. 1995 May;80(5):1496-501. PMID:7538143
  18. Desbois-Mouthon C, Sert-Langeron C, Magre J, Oreal E, Blivet MJ, Flori E, Besmond C, Capeau J, Caron M. Deletion of Asn281 in the alpha-subunit of the human insulin receptor causes constitutive activation of the receptor and insulin desensitization. J Clin Endocrinol Metab. 1996 Feb;81(2):719-27. PMID:8636294
  19. Kadowaki H, Takahashi Y, Ando A, Momomura K, Kaburagi Y, Quin JD, MacCuish AC, Koda N, Fukushima Y, Taylor SI, Akanuma Y, Yazaki Y, Kadowaki T. Four mutant alleles of the insulin receptor gene associated with genetic syndromes of extreme insulin resistance. Biochem Biophys Res Commun. 1997 Aug 28;237(3):516-20. PMID:9299395 doi:S0006-291X(97)97181-3
  20. Desbois-Mouthon C, Girodon E, Ghanem N, Caron M, Pennerath A, Conteville P, Magre J, Besmond C, Goossens M, Capeau J, Amselem S. Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families. Prenat Diagn. 1997 Jul;17(7):657-63. PMID:9249867
  21. Whitehead JP, Soos MA, Jackson R, Tasic V, Kocova M, O'Rahilly S. Multiple molecular mechanisms of insulin receptor dysfunction in a patient with Donohue syndrome. Diabetes. 1998 Aug;47(8):1362-4. PMID:9703342
  22. George S, Johansen A, Soos MA, Mortensen H, Gammeltoft S, Saudek V, Siddle K, Hansen L, O'Rahilly S. Deletion of V335 from the L2 domain of the insulin receptor results in a conformationally abnormal receptor that is unable to bind insulin and causes Donohue's syndrome in a human subject. Endocrinology. 2003 Feb;144(2):631-7. PMID:12538626
  23. Maassen JA, Tobias ES, Kayserilli H, Tukel T, Yuksel-Apak M, D'Haens E, Kleijer WJ, Fery F, van der Zon GC. Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. J Clin Endocrinol Metab. 2003 Sep;88(9):4251-7. PMID:12970295
  24. Cocozza S, Porcellini A, Riccardi G, Monticelli A, Condorelli G, Ferrara A, Pianese L, Miele C, Capaldo B, Beguinot F, et al.. NIDDM associated with mutation in tyrosine kinase domain of insulin receptor gene. Diabetes. 1992 Apr;41(4):521-6. PMID:1607076
  25. Kasuga M, Kishimoto M, Hashiramoto M, Yonezawa K, Kazumi T, Hagino H, Shii K. [Insulin receptor Arg1131-->Gln: a novel mutation in the catalytic loop of insulin receptor observed in insulin resistant diabetes] Nippon Geka Gakkai Zasshi. 1992 Sep;93(9):968-71. PMID:1470163
  26. Kan M, Kanai F, Iida M, Jinnouchi H, Todaka M, Imanaka T, Ito K, Nishioka Y, Ohnishi T, Kamohara S, et al.. Frequency of mutations of insulin receptor gene in Japanese patients with NIDDM. Diabetes. 1995 Sep;44(9):1081-6. PMID:7657032
  27. Hojlund K, Hansen T, Lajer M, Henriksen JE, Levin K, Lindholm J, Pedersen O, Beck-Nielsen H. A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes. 2004 Jun;53(6):1592-8. PMID:15161766
  28. Kasuya J, Paz IB, Maddux BA, Goldfine ID, Hefta SA, Fujita-Yamaguchi Y. Characterization of human placental insulin-like growth factor-I/insulin hybrid receptors by protein microsequencing and purification. Biochemistry. 1993 Dec 14;32(49):13531-6. PMID:8257688
  29. Soos MA, Field CE, Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. Biochem J. 1993 Mar 1;290 ( Pt 2):419-26. PMID:8452530
  30. Van Horn DJ, Myers MG Jr, Backer JM. Direct activation of the phosphatidylinositol 3'-kinase by the insulin receptor. J Biol Chem. 1994 Jan 7;269(1):29-32. PMID:8276809
  31. Sawka-Verhelle D, Filloux C, Tartare-Deckert S, Mothe I, Van Obberghen E. Identification of Stat 5B as a substrate of the insulin receptor. Eur J Biochem. 1997 Dec 1;250(2):411-7. PMID:9428692
  32. Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999 May;19(5):3278-88. PMID:10207053
  33. Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem. 2002 Oct 18;277(42):39684-95. Epub 2002 Jul 22. PMID:12138094 doi:10.1074/jbc.M202766200
  34. Fiory F, Alberobello AT, Miele C, Oriente F, Esposito I, Corbo V, Ruvo M, Tizzano B, Rasmussen TE, Gammeltoft S, Formisano P, Beguinot F. Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by the insulin receptor is necessary for insulin metabolic signaling. Mol Cell Biol. 2005 Dec;25(24):10803-14. PMID:16314505 doi:10.1128/MCB.25.24.10803-10814.2005
  35. Slaaby R, Schaffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS, Brandt J. Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem. 2006 Sep 8;281(36):25869-74. Epub 2006 Jul 10. PMID:16831875 doi:10.1074/jbc.M605189200

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