Structural Basis for Selectivity and Diversity in Angiotensin II Receptors

Angiotensin II receptors, AT(1)R and AT(2)R, serve as key components of the renin-angiotensin-aldosterone system. While AT(1)R plays a central role in the regulation of blood pressure, the function of AT(2)R is enigmatic with a variety of reported effects. To elucidate the mechanisms for the functional diversity and ligand selectivity between these receptors, we report crystal structures of the human AT(2)R bound to an AT(2)R-selective and an AT(1)R/AT(2)R-dual ligand, respectively, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins/β-arrestins, in agreement with the lack of signaling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the interactions critical for ligand binding and selectivity. Our results thus provide insights into the structural basis for distinct functions of the angiotensin receptors, and may guide the design of novel selective ligands.