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J Biol Chem. 2013 Mar 1;288(9):6116-29. doi: 10.1074/jbc.M112.431312. Epub 2013 Jan 9.

Enhanced SH3/linker interaction overcomes Abl kinase activation by gatekeeper and myristic acid binding pocket mutations and increases sensitivity to small molecule inhibitors.

Author information

1
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, USA.

Abstract

Multidomain kinases such as c-Src and c-Abl are regulated by complex allosteric interactions involving their noncatalytic SH3 and SH2 domains. Here we show that enhancing natural allosteric control of kinase activity by SH3/linker engagement has long-range suppressive effects on the kinase activity of the c-Abl core. Surprisingly, enhanced SH3/linker interaction also dramatically sensitized the Bcr-Abl tyrosine kinase associated with chronic myelogenous leukemia to small molecule inhibitors that target either the active site or the myristic acid binding pocket in the kinase domain C-lobe. Dynamics analyses using hydrogen exchange mass spectrometry revealed a remarkable allosteric network linking the SH3 domain, the myristic acid binding pocket, and the active site of the c-Abl core, providing a structural basis for the biological observations. These results suggest a rational strategy for enhanced drug targeting of Bcr-Abl and other multidomain kinase systems that use multiple small molecules to exploit natural mechanisms of kinase control.

PMID:
23303187
PMCID:
PMC3585049
DOI:
10.1074/jbc.M112.431312
[Indexed for MEDLINE]
Free PMC Article

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