| Crystal structure of the Apo, unactivated insulin-like growth factor-1 receptor kinase. Implication for inhibitor specificity. | |
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MedLine Citation:
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PMID: 12138114 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The x-ray structure of the unactivated kinase domain of insulin-like growth factor-1 receptor (IGFRK-0P) is reported here at 2.7 A resolution. IGFRK-0P is composed of two lobes connected by a hinge region. The N-terminal lobe of the kinase is a twisted beta-sheet flanked by a single helix, and the C-terminal lobe comprises eight alpha-helices and four short beta-strands. The ATP binding pocket and the catalytic center reside at the interface of the two lobes. Despite the overall similarity to other receptor tyrosine kinases, three notable conformational modifications are observed: 1) this kinase adopts a more closed structure, with its two lobes rotated further toward each other; 2) the conformation of the proximal end of the activation loop (residues 1121-1129) is different; 3) the orientation of the nucleotide-binding loop is altered. Collectively, these alterations lead to a different ATP-binding pocket that might impact on inhibitor designs for IGFRK-0P. Two molecules of IGFRK-0P are seen in the asymmetric unit; they are associated as a dimer with their ATP binding clefts facing each other. The ordered N terminus of one monomer approaches the active site of the other, suggesting that the juxtamembrane region of one molecule could come into close proximity to the active site of the other. |
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Authors:
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Sanjeev Munshi; Maria Kornienko; Dawn L Hall; John C Reid; Lloyd Waxman; Steven M Stirdivant; Paul L Darke; Lawrence C Kuo |
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Publication Detail:
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Type: Journal Article Date: 2002-07-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 277 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2002 Oct |
Date Detail:
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Created Date: 2002-10-07 Completed Date: 2002-11-25 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 38797-802 Citation Subset: IM |
Affiliation:
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Department of Structural Biology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Animals Binding Sites Crystallography, X-Ray Dimerization Insects / enzymology Models, Molecular Protein Structure, Quaternary Protein Structure, Tertiary* Receptor, IGF Type 1 / antagonists & inhibitors, chemistry*, genetics |
| Chemical | |
Reg. No./Substance:
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56-65-5/Adenosine Triphosphate; EC 2.7.10.1/Receptor, IGF Type 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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