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

Abstract

Significance Current understanding of the interactions of Abelson tyrosine kinase (c-Abl) and other kinases with inhibitors is largely based on crystallographic structures. These present frozen snapshots of molecules and may not always reflect physiologically relevant conformations and dynamics. Our solution NMR study of various c-Abl complexes with allosteric and ATP-competitive inhibitors reveals a dynamic equilibrium between several c-Abl conformations that is distinctly modulated by both types of inhibitors. The observation of a hitherto unknown open state of the c-Abl•imatinib complex can explain an unusual dose–response in cellular inhibition assays. Our data provide detailed insight into the combined effect of the two inhibitor types, which is able to overcome drug resistance. This may have important implications for the development of new drugs.