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

摘要: Successful treatment of chronic myelogenous leukemia is based on inhibitors binding to the ATP site deregulated breakpoint cluster region (Bcr)–Abelson tyrosine kinase (Abl) fusion protein. Recently, a new type allosteric targeting Abl myristoyl pocket was shown in preclinical studies overcome ATP-site inhibitor resistance arising some patients. Using NMR and small-angle X-ray scattering, we have analyzed solution conformations apo Abelson (c-Abl) c-Abl complexes with inhibitors. Binding imatinib leads an unexpected open conformation multidomain SH3-SH2-kinase core, whose relevance confirmed by cellular assays Bcr-Abl. The combination GNF-5 restores closed, inactivated state. Our data provide detailed insights poorly understood combined effect two types, which able drug resistance.