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

Laura M. Wingler https://orcid.org/0000-0002-3688-5088, Meredith A. Skiba https://orcid.org/0000-0003-4615-6775, Conor McMahon https://orcid.org/0000-0001-9971-7869, Dean P. Staus, Alissa L. W. Kleinhenz https://orcid.org/0000-0001-5871-8216, Carl-Mikael Suomivuori https://orcid.org/0000-0002-2445-8791, Naomi R. Latorraca https://orcid.org/0000-0002-8310-8708, Ron O. Dror https://orcid.org/0000-0002-6418-2793, Robert J. Lefkowitz https://orcid.org/0000-0003-1472-7545 [email protected], and Andrew C. Kruse https://orcid.org/0000-0002-1467-1222 [email protected]
Science • 21 Feb 2020 • Vol 367, Issue 6480 • pp. 888-892 • DOI: 10.1126/science.aay9813
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Choosing the drug to fit the protein

Many approved drugs bind to G protein–coupled receptors (GPCRs). A challenge in targeting GPCRs is that different ligands preferentially activate different signaling pathways. Two papers show how biased signaling arises for the angiotensin II type 1 receptor that couples to two signaling partners (G proteins and arrestins). Suomivuori et al. used large-scale atomistic simulations to show that coupling to the two pathways is through two distinct GPCR conformations and that extracellular ligands favor one or the other conformation. Wingler et al. present crystal structures of the same receptor bound to ligands with different bias profiles. These structures show conformational changes in and around the binding pocket that match those observed in simulations. This work could provide a framework for the rational design of drugs that are more effective and have fewer side effects.
Science, this issue p. 881, p. 888

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.
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Supplementary Material

Summary

Materials and Methods
Figs. S1 to S7
Tables S1 to S5
References (37–48)

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References and Notes

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Published In

Science
Volume 367 | Issue 6480
21 February 2020

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Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 2 August 2019
Accepted: 23 January 2020
Published in print: 21 February 2020

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Acknowledgments

We thank V. Brennand, Q. Lennon, and J. Taylor for administrative assistance. We thank the staff at Advanced Photon Source GM/CA beamlines for technical assistance and support of data collection. GM/[email protected] is supported by the NIH National Institute of General Medical Sciences (AGM-12006) and the National Cancer Institute (ACB-12002). Funding: Funding was provided by the Sigrid Jusélius Foundation (C.-M.S.); the International Human Frontier Science Program Organization (LT000916/2018-L) (C.-M.S.); the Mandel Center for Hypertension and Atherosclerosis at Duke (R.J.L.); the Vallee Foundation (A.C.K.); the Smith Family Foundation (A.C.K.); and NIH grants R01GM127359 (R.O.D.), R01HL16037 (R.J.L.), and DP5OD021345 (A.C.K.). A.L.W.K. is a Howard Hughes Medical Institute Medical Research Fellow. R.J.L. is an investigator with the Howard Hughes Medical Institute. Author contributions: L.M.W., D.P.S., and A.L.W.K. performed signaling and functional characterization experiments. L.M.W. crystallized the complexes. L.M.W., C.M., and A.C.K. collected x-ray diffraction data. M.A.S., C.M., and A.C.K. performed x-ray data processing and refinement. C.-M.S., N.R.L., and R.O.D. proposed experiments on the basis of structural analysis. All authors interpreted data. R.J.L. and A.C.K. supervised the project. All authors wrote the manuscript. Competing interests: R.J.L. is a founder and stockholder of Trevena and is a director of Lexicon Pharmaceuticals. A.C.K. is an advisor for the Institute for Protein Innovation, a nonprofit research institute. Data and materials availability: Coordinates and structure factors for the AT1R-AT110i1 complexes with AngII, TRV023, and TRV026 ligands are deposited in the Protein Data Bank under accession codes 6OS0, 6OS1, and 6OS2, respectively.

Authors

Affiliations

Laura M. Wingler* https://orcid.org/0000-0002-3688-5088
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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Meredith A. Skiba* https://orcid.org/0000-0003-4615-6775
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
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Conor McMahon https://orcid.org/0000-0001-9971-7869
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
View all articles by this author
Dean P. Staus
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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Alissa L. W. Kleinhenz https://orcid.org/0000-0001-5871-8216
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
View all articles by this author
Carl-Mikael Suomivuori https://orcid.org/0000-0002-2445-8791
Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
View all articles by this author
Naomi R. Latorraca https://orcid.org/0000-0002-8310-8708
Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
Biophysics Program, Stanford University, Stanford, CA 94305, USA.
Present address: Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA.
View all articles by this author
Ron O. Dror https://orcid.org/0000-0002-6418-2793
Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
Biophysics Program, Stanford University, Stanford, CA 94305, USA.
View all articles by this author
Robert J. Lefkowitz‡ https://orcid.org/0000-0003-1472-7545 [email protected]
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
View all articles by this author
Andrew C. Kruse‡ https://orcid.org/0000-0002-1467-1222 [email protected]
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
View all articles by this author

Funding Information

Mandel Center for Hypertension and Atherosclerosis at Duke
Sigrid Jusélius Foundation
International Human Frontier Science Program Organization: LT000916/2018-L

Notes

*
These authors contributed equally to this work.
‡Corresponding author. Email: [email protected] (R.J.L.); [email protected] (A.C.K.)

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