Simulation of spontaneous G protein activation reveals a new intermediate driving GDP unbinding.

ABSTRACT: Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of structural and biochemical data. Surprisingly, the rate-limiting step for GDP release correlates with tilting rather than translation of the GPCR-binding helix 5. β-Strands 1 - 3 and helix 1 emerge as hubs in the allosteric network that links conformational changes in the GPCR-binding site to disorderi

SUBMITTER: Sun X 

PROVIDER: S-EPMC6224197 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature