1t45

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spinqualitylabelsall models 1t45, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE

Overview

The activity of the c-Kit receptor protein-tyrosine kinase is tightly, regulated in normal cells, whereas deregulated c-Kit kinase activity is, implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane, region is known to have an autoinhibitory function; however the precise, mechanism by which c-Kit is maintained in an autoinhibited state is not, known. We report the 1.9-A resolution crystal structure of native c-Kit, kinase in an autoinhibited conformation and compare it with active c-Kit, kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the, activated structure. A 1.6-A crystal structure of c-Kit in complex with, STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts, this natural mechanism for maintaining c-Kit in an autoinhibited state., Together, these results provide a structural basis for understanding c-Kit, kinase autoinhibition and will facilitate the structure-guided design of, specific inhibitors that target the activated and autoinhibited, conformations of c-Kit kinase.

About this Structure

1T45 is a Single protein structure of sequence from Homo sapiens. 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

Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase., Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN, Snell GP, Zou H, Sang BC, Wilson KP, J Biol Chem. 2004 Jul 23;279(30):31655-63. Epub 2004 Apr 29. PMID:15123710

Page seeded by OCA on Wed Nov 21 02:58:28 2007