Receptor-mediated activation of heterotrimeric G-proteins: Current structural insights

G-protein-coupled receptors (GPCRs) serve as catalytic activators of heterotrimeric G-proteins (G alpha beta gamma) by exchanging GTP for the bound GDP on the G alpha subunit. This guanine nucleotide exchange factor activity of GPCRs is the initial step in the G-protein cycle and determines the onset of various intracellular signaling pathways that govern critical physiological responses to extracellular cues. Although the structural basis for many steps in the G-protein nucleotide cycle have been made clear over the past decade, the precise mechanism for receptor-mediated G-protein activation remains incompletely defined. Given that these receptors have historically represented a set of rich drug targets, a more complete understanding of their mechanism of action should provide further avenues for drug discovery. Several models have been proposed to explain the communication between activated GPCRs and G alpha beta gamma leading to the structural changes required for guanine nucleotide exchange. This review is focused on the structural biology of G-protein signal transduction with an emphasis on the current hypotheses regarding G alpha beta gamma activation. We highlight several recent results shedding new light on the structural changes in G alpha that may underlie GDP release.