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Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity

While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, w...

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Autores principales: Kapoor, Abhijeet, Martinez-Rosell, Gerard, Provasi, Davide, de Fabritiis, Gianni, Filizola, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595830/
https://www.ncbi.nlm.nih.gov/pubmed/28900175
http://dx.doi.org/10.1038/s41598-017-11483-8
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author Kapoor, Abhijeet
Martinez-Rosell, Gerard
Provasi, Davide
de Fabritiis, Gianni
Filizola, Marta
author_facet Kapoor, Abhijeet
Martinez-Rosell, Gerard
Provasi, Davide
de Fabritiis, Gianni
Filizola, Marta
author_sort Kapoor, Abhijeet
collection PubMed
description While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation.
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spelling pubmed-55958302017-09-14 Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity Kapoor, Abhijeet Martinez-Rosell, Gerard Provasi, Davide de Fabritiis, Gianni Filizola, Marta Sci Rep Article While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation. Nature Publishing Group UK 2017-09-12 /pmc/articles/PMC5595830/ /pubmed/28900175 http://dx.doi.org/10.1038/s41598-017-11483-8 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kapoor, Abhijeet
Martinez-Rosell, Gerard
Provasi, Davide
de Fabritiis, Gianni
Filizola, Marta
Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
title Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
title_full Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
title_fullStr Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
title_full_unstemmed Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
title_short Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
title_sort dynamic and kinetic elements of µ-opioid receptor functional selectivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595830/
https://www.ncbi.nlm.nih.gov/pubmed/28900175
http://dx.doi.org/10.1038/s41598-017-11483-8
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