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 AT1R and its downstream signaling proteins Gq and β‐arrestin. AT1R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT1R 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 AT1R in complex with a balanced agonist, Sar1‐AngII, and Gq protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT1R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT1R signal transduction from the ligand‐binding pocket to both Gq and β‐arrestin pathways. Specifically, we found that the MHN mutations N1113.35A and N2947.45A induce biased signaling to Gq and β‐arrestin, respectively. These insights should facilitate AT1R structure‐based drug discovery for the treatment of cardiovascular diseases. Synopsis: Angiotensin (Ang) II hormone binding to AT1R receptors activates both Gq and β‐arrestin signaling to elevate blood pressure and confer heart protection, respectively. The AT1R‐Gq‐Sar1‐AngII structure combined with functional and computational studies reveals that the crucial role of a major hydrogen bond network in biasing AT1R in either direction. A Cryo‐EM structure depicts human angiotensin II type I receptor (AT1R) activated by the balanced agonist Sar1‐AngII and coupled to its canonical transducer Gq at 2.9 Å resolution.A combination of BRET assays and molecular dynamic simulations defines the structural characteristics of Gq‐biased agonists TRV055/TRV056.A major hydrogen bond network (MHN) in the core of AT1R is crucial for AT1R signaling modulation. [ABSTRACT FROM AUTHOR]