G Protein Crystal Structure Sheds Light on Mechanism of GDP Release

Heptahelical G protein-coupled receptors (GPCRs) comprise the largest family of cell-surface receptors and are the largest target class for pharmaceutical agents.  Recently, crystal structures of several GPCRs were published in Nature, Science and other leading journals. The next frontier is to elucidate how receptors coupled to heterotrimeric G proteins to switch them from “off” to “on” in response to a signal.  What movements and conformational changes cause G proteins to release GDP and take up GTP? 
To address these questions, Neeraj Kapoor, a graduate student in the Tri-Institutional Program in Chemical Biology solved the crystal structure of an interesting mutant G protein that exhibits a very high intrinsic rate of basal nucleotide exchange.  The report of his work, published on-line in Journal of Molecular Biology, presents a detailed biochemical and biophysical analysis of an expressed Gi mutant that bears directly on the question of how the nucleotide-binding pocket of the G protein is coupled to the ligand-binding pocket of a GPCR at a distance of ~50-70 Å. 
Neeraj’s work, which was carried out with Sakmar Laboratory members Santosh Menon, Pallavi Sachdev and collaborator Radha Chauhan, extents far beyond earlier mutagenesis and structural studies of G proteins and suggests a plausible mechanistic model describing the precise steps in a sequence of conformational changes that cause GDP release.  Interestingly, the model shows striking similarities between nucleotide release by heterotrimeric G proteins and small G proteins – a finding that may have been anticipated, but was not documented earlier.  This work, which ties together mechanistic studies of GPCR- and small G-protein signaling, will be of interest to a broad group of researchers.