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Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor
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 protei...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
WILEY-VCH Verlag
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722849/ https://www.ncbi.nlm.nih.gov/pubmed/26568421 http://dx.doi.org/10.1002/anie.201508794 |
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author | 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 |
author_facet | 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 |
author_sort | Okude, Junya |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4722849 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | WILEY-VCH Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-47228492016-02-01 Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor 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 Angew Chem Int Ed Engl Communications 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. WILEY-VCH Verlag 2015-12-21 2015-11-16 /pmc/articles/PMC4722849/ /pubmed/26568421 http://dx.doi.org/10.1002/anie.201508794 Text en © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. https://creativecommons.org/licenses/by-nc/4.0/ © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Communications 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 Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor |
title | Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor |
title_full | Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor |
title_fullStr | Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor |
title_full_unstemmed | Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor |
title_short | Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor |
title_sort | identification of a conformational equilibrium that determines the efficacy and functional selectivity of the μ-opioid receptor |
topic | Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722849/ https://www.ncbi.nlm.nih.gov/pubmed/26568421 http://dx.doi.org/10.1002/anie.201508794 |
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