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Elife. 2018 Oct 5;7. pii: e38465. doi: 10.7554/eLife.38465.

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

Author information

1
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Missouri, United States.
2
Department of Cell Biology and Physiology, Washington University School of Medicine, Missouri, United States.
3
Center for Biological Systems Engineering, Washington University School of Medicine, Missouri, United States.
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Contributed equally

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 disordering of the distal nucleotide-binding site and consequent GDP release. Our approach and insights provide foundations for understanding disease-implicated G protein mutants, illuminating slow events in allosteric networks, and examining unbinding processes with slow off-rates.

KEYWORDS:

G proteins; Markov state models; allostery; computational biology; molecular biophysics; molecular dynamics; none; structural biology; systems biology

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