Abstract
c-Abl, a non-receptor tyrosine kinase, regulates cell growth and survival in healthy cells and causes chronic myeloid leukemia (CML) when fused by Bcr. Its activity is blocked in the assembled inactive state, where the SH3 and SH2 domains dock into the kinase domain, reducing its conformational flexibility, resulting in the autoinhibited state. It is active in an extended 'open' conformation. Allostery governs the transitions between the autoinhibited and active states. Even though experiments revealed the structural hallmarks of the two states, a detailed grasp of the determinants of c-Abl autoinhibition and activation at the atomic level, which may help innovative drug discovery, is still lacking. Here, using extensive molecular dynamics simulations, we decipher exactly how these determinants regulate it. Our simulations confirm and extend experimental data that the myristoyl group serves as the switch for c-Abl inhibition/activation. Its dissociation from the kinase domain promotes the SH2-SH3 release, initiating c-Abl activation. We show that the precise SH2/N-lobe interaction is required for full activation of c-Abl. It stabilizes a catalysis-favored conformation, priming it for catalytic action. Bcr-Abl allosteric drugs elegantly mimic the endogenous myristoyl-mediated autoinhibition state of c-Abl 1b. Allosteric activating mutations shift the ensemble to the active state, blocking ATP-competitive drugs. Allosteric drugs alter the active-site conformation, shifting the ensemble to re-favor ATP-competitive drugs. Our work provides a complete mechanism of c-Abl activation and insights into critical parameters controlling at the atomic level c-Abl inactivation, leading us to propose possible strategies to counter reemergence of drug resistance.