Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR

Science. 2020 Feb 21;367(6480):888-892. doi: 10.1126/science.aay9813.


Biased agonists of G protein-coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly β-arrestin-biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating β-arrestin but not heterotrimeric Gq protein signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / chemistry*
  • Humans
  • Ligands
  • Protein Conformation
  • Receptor, Angiotensin, Type 1 / chemistry*
  • Signal Transduction
  • beta-Arrestins / chemistry


  • Ligands
  • Receptor, Angiotensin, Type 1
  • beta-Arrestins
  • Angiotensin II