3d94

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Crystal structure of the insulin-like growth factor-1 receptor kinase in complex with PQIPCrystal structure of the insulin-like growth factor-1 receptor kinase in complex with PQIP

Structural highlights

3d94 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IGF1R_HUMAN Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.[1] [2]

Function

IGF1R_HUMAN Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.[3] [4] [5] [6] [7] [8] [9] [10] [11] When present in a hybrid receptor with INSR, 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.[12] [13] [14] [15] [16] [17] [18] [19] [20]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that has a critical role in mitogenic signalling during embryogenesis and an antiapoptotic role in the survival and progression of many human tumours. Here, we present the crystal structure of the tyrosine kinase domain of IGF1R (IGF1RK), in its unphosphorylated state, in complex with a novel compound, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)- imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which we show is a potent inhibitor of both the unphosphorylated (basal) and phosphorylated (activated) states of the kinase. PQIP interacts with residues in the ATP-binding pocket and in the activation loop, which confers specificity for IGF1RK and the highly related insulin receptor (IR) kinase. In this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the activation loop of an symmetry (two-fold)-related molecule. This dimeric arrangement affords, for the first time, a visualization of the initial trans-phosphorylation event in the activation loop of an RTK, and provides a molecular rationale for a naturally occurring mutation in the activation loop of the IR that causes type II diabetes mellitus.

Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor.,Wu J, Li W, Craddock BP, Foreman KW, Mulvihill MJ, Ji QS, Miller WT, Hubbard SR EMBO J. 2008 Jul 23;27(14):1985-94. Epub 2008 Jun 19. PMID:18566589[21]

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

See Also

References

  1. ↑ Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003 Dec 4;349(23):2211-22. PMID:14657428 doi:10.1056/NEJMoa010107
  2. ↑ Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J, Ohtsuka Y, Hisatome I, Ninomoya H, Nanba E, Fukushima T, Takahashi S. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab. 2005 Aug;90(8):4679-87. Epub 2005 May 31. PMID:15928254 doi:jc.2004-1947
  3. ↑ 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
  4. ↑ Tollefsen SE, Stoszek RM, Thompson K. Interaction of the alpha beta dimers of the insulin-like growth factor I receptor is required for receptor autophosphorylation. Biochemistry. 1991 Jan 8;30(1):48-54. PMID:1846292
  5. ↑ 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
  6. ↑ Kato H, Faria TN, Stannard B, Roberts CT Jr, LeRoith D. Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3). J Biol Chem. 1993 Feb 5;268(4):2655-61. PMID:7679099
  7. ↑ Baserga R. The IGF-I receptor in cancer research. Exp Cell Res. 1999 Nov 25;253(1):1-6. PMID:10579905 doi:10.1006/excr.1999.4667
  8. ↑ Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem. 2000 May 19;275(20):15099-105. PMID:10747872 doi:10.1074/jbc.M000089200
  9. ↑ 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
  10. ↑ Galvan V, Logvinova A, Sperandio S, Ichijo H, Bredesen DE. Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). J Biol Chem. 2003 Apr 11;278(15):13325-32. Epub 2003 Jan 28. PMID:12556535 doi:10.1074/jbc.M211398200
  11. ↑ 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
  12. ↑ 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
  13. ↑ Tollefsen SE, Stoszek RM, Thompson K. Interaction of the alpha beta dimers of the insulin-like growth factor I receptor is required for receptor autophosphorylation. Biochemistry. 1991 Jan 8;30(1):48-54. PMID:1846292
  14. ↑ 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
  15. ↑ Kato H, Faria TN, Stannard B, Roberts CT Jr, LeRoith D. Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3). J Biol Chem. 1993 Feb 5;268(4):2655-61. PMID:7679099
  16. ↑ Baserga R. The IGF-I receptor in cancer research. Exp Cell Res. 1999 Nov 25;253(1):1-6. PMID:10579905 doi:10.1006/excr.1999.4667
  17. ↑ Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem. 2000 May 19;275(20):15099-105. PMID:10747872 doi:10.1074/jbc.M000089200
  18. ↑ 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
  19. ↑ Galvan V, Logvinova A, Sperandio S, Ichijo H, Bredesen DE. Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). J Biol Chem. 2003 Apr 11;278(15):13325-32. Epub 2003 Jan 28. PMID:12556535 doi:10.1074/jbc.M211398200
  20. ↑ 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
  21. ↑ Wu J, Li W, Craddock BP, Foreman KW, Mulvihill MJ, Ji QS, Miller WT, Hubbard SR. Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor. EMBO J. 2008 Jul 23;27(14):1985-94. Epub 2008 Jun 19. PMID:18566589 doi:10.1038/emboj.2008.116

3d94, resolution 2.30Å

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