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 (AT(1)R) and AngII type-2 receptor (AT(2)R), are central to its mechanism of action. We solved the crystal structure of human AT(2)R bound to AngII and its specific antibody at 3.2-angstrom resolution. AngII (full agonist) and [Sar(1), Ile(8)]-AngII (partial agonist) interact with AT(2)R in a similar fashion, except at the bottom of the AT(2)R 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 AT(2)R, leading to normalization of the non-canonical coordination of helix 8. Our results will inform the design of more effective ligands for ATRs.