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

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 endo...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2020-02, Vol.367 (6480), p.888-892
Main Authors: Wingler, Laura M, Skiba, Meredith A, McMahon, Conor, Staus, Dean P, Kleinhenz, Alissa L W, Suomivuori, Carl-Mikael, Latorraca, Naomi R, Dror, Ron O, Lefkowitz, Robert J, Kruse, Andrew C
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Language:English
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Summary: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 protein signaling.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aay9813