Fig. 6. Observed intracellular conformations of AT₁R.

Simulations indicate that AT₁R adopts at least five distinct conformations that differ substantially in the intracellular positions of TM6 and TM7 and may have distinct cellular signaling profiles. In the inactive conformation (gray; illustrated by crystal structure (24)), TM6 occludes the transducer-binding pocket, hindering coupling to either G proteins or arrestins. The remaining four conformations all exhibit more outward positions of TM6 but differ substantially in the conformation of TM7, as illustrated by representative frames from our AT₁R simulations. In the middle row, we show TMs 6 and 7 of these four conformations (colors) overlaid on all TMs of the inactive structure (gray). Our results suggest that in the alternative conformation (orange), the intracellular surface hinders coupling to G proteins but allows for arrestin coupling, whereas the canonical active conformation (blue) couples to both G proteins and arrestins. Two other conformations that AT₁R adopts in simulation—the TM6-bent and non-canonical conformations, in purple and pink, respectively—have been observed in G-protein-bound structures of other GPCRs but might hinder arrestin coupling by increasing the volume of the transducer-binding pocket, preventing the arrestin finger loop from packing tightly against this pocket.