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The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation.

Cowan-Jacob, Sandra W and Fendrich, Gabriele and Manley, Paul W. and Jahnke, Wolfgang and Fabbro, Doriano and Liebetanz, Janis and Meyer, Thomas (2005) The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. Structure (London, England : 1993), 13 (6). pp. 861-871. ISSN 0969-2126

Abstract

The regulation of the activity of Abl and Src family tyrosine kinases is mediated by intramolecular interactions between the SH3, SH2, and kinase (SH1) domains. We have determined the crystal structure of an unphosphorylated form of c-Src in which the SH2 domain is not bound to the C-terminal tail. This results in an open structure where the kinase domain adopts an active conformation and the C terminus binds within a hydrophobic pocket in the C-terminal lobe. NMR binding studies support the hypothesis that an N-terminal myristate could bind in this pocket, as observed for Abl, suggesting that c-Src may also be regulated by myristate binding. In addition, the structure contains a des-methyl analog of the antileukemia drug imatinib (STI571; Gleevec). This structure reveals why the drug shows a low affinity for active kinase conformations, contributing to its excellent kinase selectivity profile.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 14 Dec 2009 13:57
Last Modified: 31 Jan 2013 01:12
URI: https://oak.novartis.com/id/eprint/617

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