Figure 1.

Activation mechanism of GPCRs involving a series of microswitches. Binding of the agonist BI-167107 leads to an inward bulge of TM5 (quantified as the distance between Ser207^5.46 and Gly315^7.41, red spheres), which leads to a conformational change in the connector region (Ile121^3.40 and Phe282^6.44, yellow spheres). The transmembrane cavity surrounding Asp79^2.50 is dehydrated (filled green circle), and the NPxxY motif (blue cartoon) twists upon activation, leading to the Y–Y interaction (Tyr326^7.53 and Tyr219^5.58, purple spheres). TM6 moves outward to create the G protein binding site. The inactive (PDB entry 2RH1(5)) and active (PDB entry 3P0G(6)) structures are colored white and orange, respectively.