Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists.

The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT 1 R and its downstream signaling proteins G q and β-arrestin. AT 1 R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT 1 R β-arrestin-biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo-electron microscopy (cryo-EM) structure of the human AT 1 R in complex with a balanced agonist, Sar 1 -AngII, and G q protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT 1 R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT 1 R signal transduction from the ligand-binding pocket to both G q and β-arrestin pathways. Specifically, we found that the MHN mutations N111 3.35 A and N294 7.45 A induce biased signaling to G q and β-arrestin, respectively. These insights should facilitate AT 1 R structure-based drug discovery for the treatment of cardiovascular diseases.