Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor

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

doi:10.1126/science.aaz0326

Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor

Science. 2020 Feb 21;367(6480):881-887. doi: 10.1126/science.aaz0326.

Authors

Carl-Mikael Suomivuori^#^{1

2

3

4}, Naomi R Latorraca^#^{1

2

3

4

5}, Laura M Wingler^{6

7}, Stephan Eismann^{1

2

3

4

8}, Matthew C King^{1

2

3

4}, Alissa L W Kleinhenz^{6

7

9}, Meredith A Skiba¹⁰, Dean P Staus^{6

7}, Andrew C Kruse¹⁰, Robert J Lefkowitz^{6

7

11}, Ron O Dror^{12

2

3

4

5}

Affiliations

¹ Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
² Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
⁵ Biophysics Program, Stanford University, Stanford, CA 94305, USA.
⁶ Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
⁷ Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
⁸ Department of Applied Physics, Stanford University, Stanford, CA 94305, USA.
⁹ School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁰ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
¹² Department of Computer Science, Stanford University, Stanford, CA 94305, USA. ron.dror@stanford.edu.

^# Contributed equally.

Abstract

Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.

Publication types

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

MeSH terms

Allosteric Regulation
Arrestins / chemistry*
GTP-Binding Proteins / chemistry*
Humans
Molecular Dynamics Simulation
Protein Conformation
Receptor, Angiotensin, Type 1 / chemistry*
Signal Transduction*

Substances

Arrestins
Receptor, Angiotensin, Type 1
GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding