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 beta-arrestin. AT(1)R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT(1)R beta-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 angstrom 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 beta-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 beta-arrestin, respectively. These insights should facilitate AT(1)R structure-based drug discovery for the treatment of cardiovascular diseases.

Automated summary

The cryo-EM structure of human AT(1)R complexed with Sar(1)-AngII and G(q) protein reveals the molecular mechanisms of AT(1)R signaling modulation and biased signaling induced by mutations in the major hydrogen bond network. These findings have implications for drug discovery in cardiovascular diseases.