![]() Additional diversity comes from differential expression of 800+ GPCRs, which includes members with little or no shared sequence similarity. The effects of G protein activation - such as vasodilation, pain reduction, euphoria as well as light and odor sensing - are quite diverse depending on the cellular context. Thus, receptors serve as signal discriminators while RGS proteins serve as timing devices and G proteins serve as determinants of output specificity. In most cases this inactivation step is accelerated by RGS proteins. Signaling is terminated after Gα hydrolyzes GTP and the heterotrimer reassembles. The Gβγ dimer can regulate many of these same effectors as well as potassium channels, calcium channels, phosphatidylinositol-3 kinase and MAPKs. The free Gα subunit then modulates the activity of downstream effector proteins such as adenylyl cyclase and phospholipase C, among others. Upon receptor activation by agonist, the G protein α subunit releases GDP, binds GTP, and dissociates from the Gβγ dimer. ![]() Receptors of this class represent one of the largest gene families, and by far the largest class of drug targets. Many hormones, neurotransmitters, and clinically important drugs elicit their effects through G protein coupled receptors (GPCRs). These findings reveal the molecular basis for the final committed step of G protein activation. ![]() Replacement of network residues prevents subunit dissociation, regardless of agonist or GTP binding. This “G-R-E motif” secures GTP and, through an allosteric link, discharges the Gβγ dimer. In the presence of the terminal phosphate of GTP, a glycine forms a polar network with an arginine and glutamate, putting torsional strain on the subunit binding interface. We use cell signaling assays, MD simulations, biochemistry and structural analysis to identify a conserved network of amino acids that dictates subunit release. In contrast, the mechanism of subunit dissociation is poorly understood. ![]() Structural studies have revealed the molecular basis for subunit association with receptors, RGS proteins and downstream effectors. ![]() Signaling is initiated by cell-surface receptors, which promote GTP binding and the dissociation of Gα from the Gβγ subunits. G proteins play a central role in signal transduction and pharmacology. ![]()
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