The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone

Angiotensin II (AngII) is a peptide hormone that plays a key role in regulating blood pressure, and its interactions with the G protein-coupled receptors, AngII type-1 receptor (AT₁R) and AngII type-2 receptor (AT₂R), are central to its mechanism of action. We solved the crystal structure of human AT₂R bound to AngII and its specific antibody at 3.2-Å resolution. AngII (full agonist) and [Sar¹, Ile⁸]-AngII (partial agonist) interact with AT₂R in a similar fashion, except at the bottom of the AT₂R ligand-binding pocket. In particular, the residues including Met128^3.36, which constitute the deep end of the cavity, play important roles in angiotensin receptor (ATR) activation upon AngII binding. These differences that occur upon endogenous ligand binding may contribute to a structural change in AT₂R, leading to normalization of the non-canonical coordination of helix 8. Our results will inform the design of more effective ligands for ATRs.