2. Academic Validation
  3. Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR

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

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. lefko001@receptor-biol.duke.edu andrew_kruse@hms.harvard.edu.
  • 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. lefko001@receptor-biol.duke.edu andrew_kruse@hms.harvard.edu.
  • # 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.

Figures