Angiotensin receptor conformations stabilized by biased ligands differentially modulate β-arrestin interactions

"Biased" ligands of the angiotensin II type 1 receptor (AT1R) preferentially activate G protein or {beta}-arrestin pathways by stabilizing distinct receptor conformations. Here we show that {beta}-arrestin-biased AT1R ligands further vary in their ability to stabilize different modes of {beta}-arrestin interaction, specifically interactions with the AT1R seven-transmembrane core versus the phosphorylated C-terminus. By combining biochemical assays with double electron-electron resonance (DEER) spectroscopy and integrative modeling, we show that ligands less effective at stabilizing the core complex promote an AT1R conformation with an intermediate transmembrane helix 6 position that is incompatible with {beta}-arrestin core binding. Since the core and phosphosite interactions differentially activate the signaling, internalization, and desensitization functions of {beta}-arrestin, our data demonstrate that the allosteric effects of GPCR ligands could directly modulate {beta}-arrestin activities. This "intra-transducer bias," or bias toward various functions of the same transducer, could enable finer control of GPCR drugs pharmacology than previously thought possible.