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Science. 2015 Jun 19;348(6241):1361-5. doi: 10.1126/science.aaa5264.

SIGNAL TRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric G proteins.

Author information

1
D. E. Shaw Research, New York, NY 10036, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com.
2
D. E. Shaw Research, New York, NY 10036, USA.
3
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5
Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
6
D. E. Shaw Research, New York, NY 10036, USA. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com.

Abstract

G protein-coupled receptors (GPCRs) relay diverse extracellular signals into cells by catalyzing nucleotide release from heterotrimeric G proteins, but the mechanism underlying this quintessential molecular signaling event has remained unclear. Here we use atomic-level simulations to elucidate the nucleotide-release mechanism. We find that the G protein α subunit Ras and helical domains-previously observed to separate widely upon receptor binding to expose the nucleotide-binding site-separate spontaneously and frequently even in the absence of a receptor. Domain separation is necessary but not sufficient for rapid nucleotide release. Rather, receptors catalyze nucleotide release by favoring an internal structural rearrangement of the Ras domain that weakens its nucleotide affinity. We use double electron-electron resonance spectroscopy and protein engineering to confirm predictions of our computationally determined mechanism.

PMID:
26089515
PMCID:
PMC4968074
DOI:
10.1126/science.aaa5264
[Indexed for MEDLINE]
Free PMC Article

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