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

Science, ISSN: 1095-9203, Vol: 367, Issue: 6480, Page: 888-892
2020
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Article Description

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 b-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 b-arrestin but not heterotrimeric G protein signaling.

Bibliographic Details

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

American Association for the Advancement of Science (AAAS)

Multidisciplinary

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