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.
Laura M Wingler  #  1  2 ,  Meredith A Skiba  #  3 ,  Conor McMahon  3 ,  Dean P Staus  1  2 ,  Alissa L W Kleinhenz  1  2  4 ,  Carl-Mikael Suomivuori  5  6  7 ,  Naomi R Latorraca  5  6  7  8 ,  Ron O Dror  5  6  7  8 ,  Robert J Lefkowitz  9  2  10 ,  Andrew C Kruse  11
Affiliations
  • 1. Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
  • 2. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
  • 3. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 4. School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5. Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
  • 6. Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 7. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
  • 8. Biophysics Program, Stanford University, Stanford, CA 94305, USA.
  • 9. Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA. [email protected] [email protected].
  • 10. Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
  • 11. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. [email protected] [email protected].
  • # Contributed equally.
PMID: 32079768 DOI: 10.1126/science.aay9813
Abstract

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.