期刊
ELIFE
卷 7, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.38465
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资金
- National Institutes of Health [R01GM12400701, R01GM044592, R01GM12409301]
- National Science Foundation CAREER Award [CB1552471]
- David and Lucile Packard Foundation Packard Fellowship for Science and Engineering
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM044592, R01GM124007, R01GM124093] Funding Source: NIH RePORTER
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 similar to 30 angstrom 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. beta-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.
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