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

Abstract 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.