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 AT₁ R and its downstream signaling proteins G_q and β-arrestin. AT₁ R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT₁ 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 AT₁ R in complex with a balanced agonist, Sar¹ -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 AT₁ R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT₁ 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 AT₁ R structure-based drug discovery for the treatment of cardiovascular diseases.