A receptor that might block itself

Abstract

The structure of the angiotensin II type 2 receptor reveals a potential mode of self-blocking action. This might explain its lack of signalling, and opens up avenues of investigation into its function and role in disease. See Article p.327 The angiotensin receptors AT1R and AT2R are G-protein-coupled receptors (GPCRs) with important roles in blood pressure regulation. Although AT2R is an important drug target for cardioprotection and for treating neuropathic pain and is believed to counteract several effects mediated by AT1R, its structure and function are not well understood. In this work, the authors report several crystal structures of AT2R in complex with two tightly bound ligands. These structures show a significant conformational rearrangement of the transmembrane helices to an active-like state that is similar to other class A GPCRs, save for one remarkable difference. In the active-like conformation, helix VIII adopts a non-canonical position, which not only stabilizes the state but also blocks the canonical signalling pathway of GPCRs by preventing binding of the G protein and β-arrestin. This challenges the notion of differentiating these ligands as 'agonists' or 'antagonists', or terming the state as 'active', as it precludes signalling partner interactions.