SIGNAL TRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science 2015 Jun 19;348(6241):1361-5
Date
06/20/2015Pubmed ID
26089515Pubmed Central ID
PMC4968074DOI
10.1126/science.aaa5264Scopus ID
2-s2.0-84932647495 (requires institutional sign-in at Scopus site) 233 CitationsAbstract
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.
Author List
Dror RO, Mildorf TJ, Hilger D, Manglik A, Borhani DW, Arlow DH, Philippsen A, Villanueva N, Yang Z, Lerch MT, Hubbell WL, Kobilka BK, Sunahara RK, Shaw DEAuthor
Michael Lerch PhD Associate Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
GTP-Binding Protein alpha Subunits, Gi-GoGTP-Binding Protein alpha Subunits, Gs
Guanine Nucleotide Exchange Factors
Humans
Models, Chemical
Molecular Dynamics Simulation
Protein Structure, Secondary
Protein Structure, Tertiary
Receptors, G-Protein-Coupled
Signal Transduction
