title: Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Junya
authors.initials: J
authors.lastname: Okude
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0075 (Japan).
authors.forename: Takumi
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kofuku
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nobuyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Keita
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Takuya
authors.initials: T
authors.lastname: Mizumura
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Kento
authors.initials: K
authors.lastname: Onishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Mei
authors.initials: M
authors.lastname: Natsume
authors.affiliation: Shionogi Co., Ltd., Discovery Research Laboratories, Osaka 561-0825 (Japan).
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Shionogi Co., Ltd., Discovery Research Laboratories, Osaka 561-0825 (Japan).
authors.forename: Hideki
authors.initials: H
authors.lastname: Tsujishita
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kuranaga
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033 (Japan). shimada@iw-nmr.f.u-tokyo.ac.jp.
authors.forename: Ichio
authors.initials: I
authors.lastname: Shimada
mesh_terms: D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D017450:Receptors, Opioid, mu / Q000737:chemistry*
chemical_list: D017450:Receptors, Opioid, mu
keywords: G-protein-coupled receptors; NMR spectroscopy; isotopic labeling; lipid bilayers; membrane proteins