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J. Biol. Chem., Vol. 277, Issue 41, 38797-38802, October 11, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/41/38797    most recent M205580200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Munshi, S. Articles by Kuo, L. C. Search for Related Content PubMed PubMed Citation Articles by Munshi, S. Articles by Kuo, L. C. Social Bookmarking                      What's this?

Crystal Structure of the Apo, Unactivated Insulin-like Growth Factor-1 Receptor Kinase
IMPLICATION FOR INHIBITOR SPECIFICITY^*

Sanjeev Munshi, Maria Kornienko, Dawn L. Hall, John C. Reid, Lloyd Waxman, Steven M. Stirdivant, Paul L. Darke, and Lawrence C. Kuo

From the Department of Structural Biology and  Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486

The x-ray structure of the unactivated kinase domain of insulin-like growth factor-1 receptor (IGFRK-0P) is reported here at 2.7 Å resolution. IGFRK-0P is composed of two lobes connected by a hinge region. The N-terminal lobe of the kinase is a twisted -sheet flanked by a single helix, and the C-terminal lobe comprises eight -helices and four short -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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