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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wingler, LM; Skiba, MA; McMahon, C; Staus, DP; Kleinhenz, ALW; Suomivuori, C-M; Latorraca, NR; Dror, RO; Lefkowitz, RJ; Kruse, AC

Published Date

  • February 21, 2020

Published In

Volume / Issue

  • 367 / 6480

Start / End Page

  • 888 - 892

PubMed ID

  • 32079768

Pubmed Central ID

  • 32079768

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

Digital Object Identifier (DOI)

  • 10.1126/science.aay9813

Language

  • eng

Conference Location

  • United States