Dynamic and kinetic elements of μ-opioid receptor functional selectivity

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  • dc.contributor.author Kapoor, Abhijeetca
  • dc.contributor.author Martínez Rosell, Gerard, 1990-ca
  • dc.contributor.author Provasi, Davideca
  • dc.contributor.author De Fabritiis, Giannica
  • dc.contributor.author Filizola, Martaca
  • dc.date.accessioned 2017-11-14T09:21:31Z
  • dc.date.available 2017-11-14T09:21:31Z
  • dc.date.issued 2017
  • dc.description.abstract 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.
  • dc.description.sponsorship This work was supported by National Institutes of Health grants DA026434, DA034049, and MH107053(to M.F.) and by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 675451 (CompBio Med project; to G.D.F). Computations were run on resources available through the Scientific Computing Facility at Mount Sinai, the Extreme Science and Engineering Discovery Environment under MCB080077, which is supported by National Science Foundation grant number ACI-1053575, and the high-throughput molecular dynamics (HTMD) platform.
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Kapoor A, Martinez-Rosell G, Provasi D, de Fabritiis G, Filizola M. Dynamic and kinetic elements of μ-opioid receptor functional selectivity. Sci Rep. 2017 Sep 12;7(1):11255. DOI: 10.1038/s41598-017-11483-8
  • dc.identifier.doi http://dx.doi.org/10.1038/s41598-017-11483-8
  • dc.identifier.issn 2045-2322
  • dc.identifier.uri http://hdl.handle.net/10230/33214
  • dc.language.iso eng
  • dc.publisher Nature Publishing Groupca
  • dc.relation.ispartof Scientific Reports. 2017 Sep 12;7(1):11255
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/675451
  • dc.rights © 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/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Opioid analgesics
  • dc.subject.keyword Opiate agonist
  • dc.title Dynamic and kinetic elements of μ-opioid receptor functional selectivityca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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