Fig. 5: A G protein-competitive mechanism of allosteric GPCR inverse agonism.
From: An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism
In its constitutively active state (top panel), GPR61 adopts a conformation that allows binding and nucleotide exchange of the G protein complex (bottom left panel) to stimulate cyclic AMP-mediated signaling through activation of adenylate cyclase. Inverse agonist compound 1 (magenta) binds to an intracellular allosteric pocket overlapping that bound by Gαs and acts as a wedge to remodel the flanking helices (yellow arrow), destroying the Gαs-binding pocket and creating direct clashes that prevent potential Gαs binding.
