Skora, Lukasz, Jahnke, Wolfgang, Mestan, Jürgen, 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