Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors

The recent mu-opioid receptor (MOPr) and kappa-opioid receptor (KOPr) crystal structures have inspired hypotheses of physiologically relevant dimerization contacts, specifically: a closely packed interface involving transmembrane (TM) helices TM5 and TM6, and a less compact interface, involving TM1,...

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Main Authors:	Johnston, Jennifer M., Filizola, Marta
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944890/

id	pubmed-3944890
recordtype	oai_dc
spelling	pubmed-39448902014-03-10 Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors Johnston, Jennifer M. Filizola, Marta Research Article The recent mu-opioid receptor (MOPr) and kappa-opioid receptor (KOPr) crystal structures have inspired hypotheses of physiologically relevant dimerization contacts, specifically: a closely packed interface involving transmembrane (TM) helices TM5 and TM6, and a less compact interface, involving TM1, TM2, and helix 8 (H8). While the former was only found in MOPr crystals, similar arrangements of the latter were identified for both KOPr and MOPr. The relevance of these interfaces outside of a crystal lattice is called into question by the possibility that they might be influenced by the specific crystallization conditions. In this study, we have employed umbrella sampling molecular dynamics simulations of coarse-grained representations of the interacting MOPr or KOPr crystallographic structures, in the absence of the T4 lysozyme, and in an explicit lipid-water environment, to determine the strength of receptor dimerization at the different crystallographic interfaces. We note that the shape of the interface plays a dominant role in the strength of the interaction, and the pattern of contacting residues defines the shape of the potential of mean force. This information can be used to guide experiments aimed at exploring the role of dimerization in opioid receptor function. Public Library of Science 2014-02-28 /pmc/articles/PMC3944890/ /pubmed/24651466 http://dx.doi.org/10.1371/journal.pone.0090694 Text en © 2014 Johnston, Filizola http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Johnston, Jennifer M. Filizola, Marta
spellingShingle	Johnston, Jennifer M. Filizola, Marta Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors
author_facet	Johnston, Jennifer M. Filizola, Marta
author_sort	Johnston, Jennifer M.
title	Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors
title_short	Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors
title_full	Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors
title_fullStr	Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors
title_full_unstemmed	Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors
title_sort	differential stability of the crystallographic interfaces of mu- and kappa-opioid receptors
description	The recent mu-opioid receptor (MOPr) and kappa-opioid receptor (KOPr) crystal structures have inspired hypotheses of physiologically relevant dimerization contacts, specifically: a closely packed interface involving transmembrane (TM) helices TM5 and TM6, and a less compact interface, involving TM1, TM2, and helix 8 (H8). While the former was only found in MOPr crystals, similar arrangements of the latter were identified for both KOPr and MOPr. The relevance of these interfaces outside of a crystal lattice is called into question by the possibility that they might be influenced by the specific crystallization conditions. In this study, we have employed umbrella sampling molecular dynamics simulations of coarse-grained representations of the interacting MOPr or KOPr crystallographic structures, in the absence of the T4 lysozyme, and in an explicit lipid-water environment, to determine the strength of receptor dimerization at the different crystallographic interfaces. We note that the shape of the interface plays a dominant role in the strength of the interaction, and the pattern of contacting residues defines the shape of the potential of mean force. This information can be used to guide experiments aimed at exploring the role of dimerization in opioid receptor function.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944890/
_version_	1612065200923475968

Differential Stability of the Crystallographic Interfaces of Mu- and Kappa-Opioid Receptors

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