Heterotrimeric G protein activation by G-protein-coupled receptors

G-protein-coupled receptors (GPCRs) represent one of the largest and most diverse groups of proteins in the genome. Activated receptors catalyse nucleotide exchange on a relatively small group of heterotrimeric G proteins to initiate intracellular signalling.Biophysical studies of rhodopsin-family GPCRs have shown that receptor activation results in an outward movement of transmembrane helix VI, which opens a pocket for G protein binding. Increasing evidence suggests that the structure, conformation and specificity of the G protein binding site can be regulated by the identity of the bound ligand.Several different models for receptor–G-protein association have been proposed. These proteins may be precoupled in a large signalling complex. Nucleotide exchange may follow a series of transition complexes. Receptors may function as dimers to activate G proteins.Biophysical studies indicate that receptor-mediated GDP release requires a conformational change in the α5 helix of the Gα subunit and is associated with structural changes at the Gβ binding site. However, additional studies are required to fully describe the mechanism of receptor-mediated GDP release and the structure of the receptor–G-protein complex.Binding of GTP induces a structural rearrangement of the receptor–G-protein complex that leads to dissociation of some, but not all, complexes. This observation is consistent with the existence of precoupled receptor–G-protein complexes that may not completely disassemble on G protein activation.Fundamentally, the unanswered questions about G protein activation reflect a poor understanding of the structure of the complex. A goal of future studies will be to refine current models of the receptor–G-protein complex in terms of the available structural information until a crystal structure of the complex is solved.