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