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

Laura M Wingler; Meredith A Skiba; Conor McMahon; Dean P Staus; Alissa L W Kleinhenz; Carl-Mikael Suomivuori; Naomi R Latorraca; Ron O Dror; Robert J Lefkowitz; Andrew C Kruse

doi:10.1126/science.aay9813

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.

Authors

Laura M Wingler^#^{1

2}, Meredith A Skiba^#³, Conor McMahon³, 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 Kruse¹¹

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.

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 G_q 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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding