Open AccessMolecular mechanism of biased signaling in a prototypical G protein–coupled receptor
Author(s) -
CarlMikael Suomivuori,
Naomi R. Latorraca,
Laura M. Wingler,
Stephan Eismann,
Matthew C. King,
A.L.W. Kleinhenz,
Meredith A. Skiba,
Dean P. Staus,
Andrew C. Kruse,
Robert J. Lefkowitz,
Ron O. Dror
Publication year - 2020
Publication title -
science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 12.556
H-Index - 1186
eISSN - 1095-9203
pISSN - 0036-8075
DOI - 10.1126/science.aaz0326
Subject(s) - allosteric regulation , signal transduction , g protein coupled receptor , mechanism (biology) , receptor , signaling proteins , intracellular , functional selectivity , extracellular , microbiology and biotechnology , arrestin , g protein , chemistry , cell signaling , biology , biophysics , biochemistry , physics , quantum mechanics
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). Suomivuoriet 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. Wingleret 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
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