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Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ‐Opioid Receptor
Author(s) -
Okude Junya,
Ueda Takumi,
Kofuku Yutaka,
Sato Motohiko,
Nobuyama Naoyuki,
Kondo Keita,
Shiraishi Yutaro,
Mizumura Takuya,
Onishi Kento,
Natsume Mei,
Maeda Masahiro,
Tsujishita Hideki,
Kuranaga Takefumi,
Inoue Masayuki,
Shimada Ichio
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201508794
Subject(s) - g protein coupled receptor , ligand (biochemistry) , chemistry , functional selectivity , receptor , transmembrane domain , population , signal transduction , biophysics , intracellular , g protein , arrestin , transmembrane protein , stereochemistry , biology , biochemistry , medicine , environmental health
G‐protein‐coupled receptor (GPCR) ligands impart differing degrees of signaling in the G‐protein and arrestin pathways, in phenomena called “biased signaling”. However, the mechanism underlying the biased signaling of GPCRs is still unclear, although crystal structures of GPCRs bound to the G protein or arrestin are available. In this study, we observed the NMR signals from methionine residues of the μ‐opioid receptor (μOR) in the balanced‐ and biased‐ligand‐bound states. We found that the intracellular cavity of μOR exists in an equilibrium between closed and multiple open conformations with coupled conformational changes on the transmembrane helices 3, 5, 6, and 7, and that the population of each open conformation determines the G‐protein‐ and arrestin‐mediated signaling levels in each ligand‐bound state. These findings provide insight into the biased signaling of GPCRs and will be helpful for development of analgesics that stimulate μOR with reduced tolerance and dependence.