Structural Basis for Angiotensin II Type I Receptor G Protein-biased Signaling

Biased agonism at the angiotensin II type 1 receptor (AT1R) offers a promising strategy for developing safer cardiovascular therapeutics. While beta-arrestin-biased agonism has been extensively investigated, G protein-biased signaling remains poorly understood. Here, we report structures of AT1R coupled to G protein and either the endogenous agonist angiotensin II (AngII) or the G protein-biased agonist TRV055. The ligands adopt similar overall poses, with coordinated rearrangements extending from the orthosteric pocket to the intracellular surface. The structures provide a detailed view of a TM7-centered microswitch network linking ligand recognition to G protein coupling. Functional analyses of peptide analogs identify the ligand's amino terminus as a key determinant of G protein bias, while mutagenesis of the microswitch network shifts AngII toward beta-arrestin-biased signaling and converts the G protein-biased agonist TRV055 into a beta-arrestin-biased ligand. These findings establish a framework for G protein-biased AT1R activation and provide mechanistic insight for the rational design of pathway-selective GPCR therapeutics.