Simulation of the Conformational Transition Pathway for the Activation of Full-Length C-Src Kinase using the String Method

Abstract

Listen

Translate article

The Src family kinases are important cellular signaling proteins that share a common catalytic domain and two peptide-binding regulatory domains called SH2 and SH3. X-ray crystal structures of c-Src kinase are available for the inactive assembled state and an active-like re-assembled state, but the transition pathway and its dependence on the configuration of the SH2 and SH3 regulatory modules is still largely unsolved. Using molecular dynamics simulations and the string method with swarms-of-trajectories we have determined the transition pathway in both the assembled and re-assembled active-like conformations of the SH2/SH3 domains. Comparison of the active-like conformation of the catalytic domain in the two SH2/SH3 states shows that the re-assembled SH2/SH3 promotes a further opening of the catalytic site. The mechanism of the A-loop opening is also influenced by the SH2/SH3 domains. The calculated pathway provides novel insight into the influence of the regulatory models on kinase activation.