Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody

The angiotensin II (AngII) type 1 receptor (AT1R) is a critical regulator of cardiovascular and renal function and is an important model for studies of G-protein-coupled receptor (GPCR) signaling. By stabilizing the receptor with a single-domain antibody fragment (“nanobody”) discovered using a synthetic yeast-displayed library, we determined the crystal structure of active-state human AT1R bound to an AngII analog with partial agonist activity. The nanobody binds to the receptor’s intracellular transducer pocket, stabilizing the large conformational changes characteristic of activated GPCRs. The peptide engages the AT1R through an extensive interface spanning from the receptor core to its extracellular face and N terminus, remodeling the ligand-binding cavity. Remarkably, the mechanism used to propagate conformational changes through the receptor diverges from other GPCRs at several key sites, highlighting the diversity of allosteric mechanisms among GPCRs. Our structure provides insight into how AngII and its analogs stimulate full or biased signaling, respectively. [Display omitted] •Active angiotensin II type 1 receptor crystallized with angiotensin II peptide analog•Stabilized by a conformation-specific synthetic nanobody discovered by yeast display•Extensive peptide-receptor engagement remodels ligand-binding cavity•Intra- and extracellular changes give insights on GPCR activation and biased agonism Structural analysis of the interactions between the angiotensin receptor and a partial agonist shows how peptide ligands induce receptor activation.