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Activation mechanism of the μ-opioid receptor by an allosteric modulator
Allosteric modulators of G-protein-coupled receptors (GPCRs) enhance signaling by binding to GPCRs concurrently with their orthosteric ligands, offering a novel approach to overcome the efficacy limitations of conventional orthosteric ligands. However, the structural mechanism by which allosteric mo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169721/ https://www.ncbi.nlm.nih.gov/pubmed/35412886 http://dx.doi.org/10.1073/pnas.2121918119 |
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author | Kaneko, Shun Imai, Shunsuke Asao, Nobuaki Kofuku, Yutaka Ueda, Takumi Shimada, Ichio |
author_facet | Kaneko, Shun Imai, Shunsuke Asao, Nobuaki Kofuku, Yutaka Ueda, Takumi Shimada, Ichio |
author_sort | Kaneko, Shun |
collection | PubMed |
description | Allosteric modulators of G-protein-coupled receptors (GPCRs) enhance signaling by binding to GPCRs concurrently with their orthosteric ligands, offering a novel approach to overcome the efficacy limitations of conventional orthosteric ligands. However, the structural mechanism by which allosteric modulators mediate GPCR signaling remains largely unknown. Here, to elucidate the mechanism of μ-opioid receptor (MOR) activation by allosteric modulators, we conducted solution NMR analyses of MOR by monitoring the signals from methionine methyl groups. We found that the intracellular side of MOR exists in an equilibrium between three conformations with different activities. Interestingly, the populations in the equilibrium determine the apparent signaling activity of MOR. Our analyses also revealed that the equilibrium is not fully shifted to the conformation with the highest activity even in the full agonist-bound state, where the intracellular half of TM6 is outward-shifted. Surprisingly, an allosteric modulator for MOR, BMS-986122, shifted the equilibrium toward the conformation with the highest activity, leading to the increased activity of MOR in the full agonist-bound state. We also determined that BMS-986122 binds to a cleft in the transmembrane region around T162 on TM3. Together, these results suggest that BMS-986122 binding to TM3 increases the activity of MOR by rearranging the direct interactions of TM3 and TM6, thus stabilizing TM6 in the outward-shifted position which is favorable for G-protein binding. These findings shed light on the rational developments of novel allosteric modulators that activate GPCRs further than orthosteric ligands alone and pave the way for next-generation GPCR-targeting therapeutics. |
format | Online Article Text |
id | pubmed-9169721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-91697212022-10-11 Activation mechanism of the μ-opioid receptor by an allosteric modulator Kaneko, Shun Imai, Shunsuke Asao, Nobuaki Kofuku, Yutaka Ueda, Takumi Shimada, Ichio Proc Natl Acad Sci U S A Biological Sciences Allosteric modulators of G-protein-coupled receptors (GPCRs) enhance signaling by binding to GPCRs concurrently with their orthosteric ligands, offering a novel approach to overcome the efficacy limitations of conventional orthosteric ligands. However, the structural mechanism by which allosteric modulators mediate GPCR signaling remains largely unknown. Here, to elucidate the mechanism of μ-opioid receptor (MOR) activation by allosteric modulators, we conducted solution NMR analyses of MOR by monitoring the signals from methionine methyl groups. We found that the intracellular side of MOR exists in an equilibrium between three conformations with different activities. Interestingly, the populations in the equilibrium determine the apparent signaling activity of MOR. Our analyses also revealed that the equilibrium is not fully shifted to the conformation with the highest activity even in the full agonist-bound state, where the intracellular half of TM6 is outward-shifted. Surprisingly, an allosteric modulator for MOR, BMS-986122, shifted the equilibrium toward the conformation with the highest activity, leading to the increased activity of MOR in the full agonist-bound state. We also determined that BMS-986122 binds to a cleft in the transmembrane region around T162 on TM3. Together, these results suggest that BMS-986122 binding to TM3 increases the activity of MOR by rearranging the direct interactions of TM3 and TM6, thus stabilizing TM6 in the outward-shifted position which is favorable for G-protein binding. These findings shed light on the rational developments of novel allosteric modulators that activate GPCRs further than orthosteric ligands alone and pave the way for next-generation GPCR-targeting therapeutics. National Academy of Sciences 2022-04-11 2022-04-19 /pmc/articles/PMC9169721/ /pubmed/35412886 http://dx.doi.org/10.1073/pnas.2121918119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Kaneko, Shun Imai, Shunsuke Asao, Nobuaki Kofuku, Yutaka Ueda, Takumi Shimada, Ichio Activation mechanism of the μ-opioid receptor by an allosteric modulator |
title | Activation mechanism of the μ-opioid receptor by an allosteric modulator |
title_full | Activation mechanism of the μ-opioid receptor by an allosteric modulator |
title_fullStr | Activation mechanism of the μ-opioid receptor by an allosteric modulator |
title_full_unstemmed | Activation mechanism of the μ-opioid receptor by an allosteric modulator |
title_short | Activation mechanism of the μ-opioid receptor by an allosteric modulator |
title_sort | activation mechanism of the μ-opioid receptor by an allosteric modulator |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169721/ https://www.ncbi.nlm.nih.gov/pubmed/35412886 http://dx.doi.org/10.1073/pnas.2121918119 |
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