Molecular Simulations of Conformational Transitions within the Insulin Receptor Kinase Reveal Consensus Features in a Multistep Activation Pathway.

ABSTRACT: Modulating the transitions between active and inactive conformations of protein kinases is the primary means of regulating their catalytic activity, achieved by phosphorylation of the activation loop (A-loop). To elucidate the mechanism of this conformational activation, we applied the string method to determine the conformational transition path of insulin receptor kinase between the active and inactive conformations and the corresponding free-energy profiles with and without A-loop phosphorylation. The conformational change was found to proceed in three sequential steps: first, the flipping of the DFG motif of the active site; second, rotation of the A-loop; finally, the inward movement of the αC helix. The main energetic bottleneck corresponds to the conformational change in the A-loop,

SUBMITTER: Nam K 

PROVIDER: S-EPMC10332359 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature