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NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors

Skora, Lukasz and Jahnke, Wolfgang and Mestan, Jürgen and Grzesiek, Stephan and Fabbro, Doriano (2013) NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors. PNAS, 110 (47). pp. 4437-4445. ISSN 0027-84241091-6490

Abstract

Successful treatment of chronic myelogenous leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) against the deregulated Bcr-Abl kinase. Recently, a new type of allosteric inhibitors was shown to overcome TKI resistance in preclinical studies. Using NMR and small-angle X-ray scattering we have determined the solution conformations of apo c-Abl and c-Abl complexes with both types of inhibitors. Binding of the TKI imatinib leads to a previously unknown open-inhibited conformation of the SH3-SH2-kinase c-Abl core, whose relevance is confirmed by cellular assays on the Bcr-Abl oncoprotein. The combination of imatinib with the allosteric inhibitor GNF-5 restores the closed state. These data provide new insights on the poorly understood mechanism of allosteric and classical c-Abl inhibitors.

Item Type: Article
Date Deposited: 12 May 2016 23:45
Last Modified: 06 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/9754

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