Structural basis for nucleotide exchange in heterotrimeric G proteins

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 n...

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Published inScience (American Association for the Advancement of Science) Vol. 348; no. 6241; pp. 1361 - 1365
Main Authors Dror, Ron O., Mildorf, Thomas J., Hilger, Daniel, Manglik, Aashish, Borhani, David W., Arlow, Daniel H., Philippsen, Ansgar, Villanueva, Nicolas, Yang, Zhongyu, Lerch, Michael T., Hubbell, Wayne L., Kobilka, Brian K., Sunahara, Roger K., Shaw, David E.
Format Journal Article
LanguageEnglish
Published Washington American Association for the Advancement of Science 19.06.2015
The American Association for the Advancement of Science
Subjects
Binding
Computer simulation
Electrons
Exchange
Guanosines
Nucleotides
Proteins
Receptors
Simulation
Spectroscopy
Spectrum analysis
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Summary: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 a 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.
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These authors contributed equally to the manuscript.
Current address: Department of Computer Science, Department of Molecular and Cellular Physiology, and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA
Current address: Biophysics Graduate Group, University of California, Berkeley, CA 94720, USA
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aaa5264