Allosteric regulation of autoinhibition and activation of c-Abl.

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 determi

SUBMITTER: Liu Y 

PROVIDER: S-EPMC9399898 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature