1jqh

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==Overview==
==Overview==
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BACKGROUND: The insulin-like growth-factor-1 (IGF-1) receptor, which is, widely expressed in cells that have undergone oncogenic transformation, is, emerging as a novel target in cancer therapy. IGF-1-induced receptor, activation results in autophosphorylation of cytoplasmic kinase domains, and enhances their capability to phosphorylate downstream substrates., Structures of the homologous insulin receptor kinase (IRK) exist in an, open, unphosphorylated form and a closed, trisphosphorylated form., RESULTS: We have determined the 2.1 A crystal structure of the IGF-1, receptor protein tyrosine kinase domain phosphorylated at two tyrosine, residues within the activation loop (IGF-1RK2P) and bound to an ATP, analog. The ligand is not in a conformation compatible with phosphoryl, transfer, and the activation loop is partially disordered. Compared to the, homologous insulin receptor kinase, IGF-1RK2P is trapped in a half-closed, previously unobserved conformation. Observed domain movements can be, dissected into two orthogonal rotational components. CONCLUSIONS:, Conformational changes upon kinase activation are triggered by the degree, of phosphorylation and are crucially dependent on the conformation of the, proximal end of the kinase activation loop. This IGF-1RK structure will, provide a molecular basis for the design of selective antioncogenic, therapeutic agents.
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BACKGROUND: The insulin-like growth-factor-1 (IGF-1) receptor, which is widely expressed in cells that have undergone oncogenic transformation, is emerging as a novel target in cancer therapy. IGF-1-induced receptor activation results in autophosphorylation of cytoplasmic kinase domains and enhances their capability to phosphorylate downstream substrates. Structures of the homologous insulin receptor kinase (IRK) exist in an open, unphosphorylated form and a closed, trisphosphorylated form. RESULTS: We have determined the 2.1 A crystal structure of the IGF-1 receptor protein tyrosine kinase domain phosphorylated at two tyrosine residues within the activation loop (IGF-1RK2P) and bound to an ATP analog. The ligand is not in a conformation compatible with phosphoryl transfer, and the activation loop is partially disordered. Compared to the homologous insulin receptor kinase, IGF-1RK2P is trapped in a half-closed, previously unobserved conformation. Observed domain movements can be dissected into two orthogonal rotational components. CONCLUSIONS: Conformational changes upon kinase activation are triggered by the degree of phosphorylation and are crucially dependent on the conformation of the proximal end of the kinase activation loop. This IGF-1RK structure will provide a molecular basis for the design of selective antioncogenic therapeutic agents.
==Disease==
==Disease==
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[[Category: protein kinase fold]]
[[Category: protein kinase fold]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:08:48 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:25:37 2008''

Revision as of 11:25, 21 February 2008

Image:1jqh.jpg

1jqh, resolution 2.10Å

Drag the structure with the mouse to rotate

IGF-1 receptor kinase domain

Contents

Overview

BACKGROUND: The insulin-like growth-factor-1 (IGF-1) receptor, which is widely expressed in cells that have undergone oncogenic transformation, is emerging as a novel target in cancer therapy. IGF-1-induced receptor activation results in autophosphorylation of cytoplasmic kinase domains and enhances their capability to phosphorylate downstream substrates. Structures of the homologous insulin receptor kinase (IRK) exist in an open, unphosphorylated form and a closed, trisphosphorylated form. RESULTS: We have determined the 2.1 A crystal structure of the IGF-1 receptor protein tyrosine kinase domain phosphorylated at two tyrosine residues within the activation loop (IGF-1RK2P) and bound to an ATP analog. The ligand is not in a conformation compatible with phosphoryl transfer, and the activation loop is partially disordered. Compared to the homologous insulin receptor kinase, IGF-1RK2P is trapped in a half-closed, previously unobserved conformation. Observed domain movements can be dissected into two orthogonal rotational components. CONCLUSIONS: Conformational changes upon kinase activation are triggered by the degree of phosphorylation and are crucially dependent on the conformation of the proximal end of the kinase activation loop. This IGF-1RK structure will provide a molecular basis for the design of selective antioncogenic therapeutic agents.

Disease

Known disease associated with this structure: Intrauterine and postnatal growth retardation OMIM:[147370]

About this Structure

1JQH is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

Reference

Crystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation., Pautsch A, Zoephel A, Ahorn H, Spevak W, Hauptmann R, Nar H, Structure. 2001 Oct;9(10):955-65. PMID:11591350

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