Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain
As a class C GPCR and regulator of synaptic activity, mGlu5 is an attractive drug target, potentially offering treatment for several neurologic and psychiatric disorders. As little is known about the activation mechanism of mGlu5 at a structural level, potential of mean force calculations linked to...
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doaj-1e8feb3199bf4434bfe33b98033506282020-11-25T02:13:57ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-03-01710.3389/fmolb.2020.00038513462Exploring the Activation Mechanism of the mGlu5 Transmembrane DomainIsaias Lans0Isaias Lans1Óscar Díaz2Óscar Díaz3Óscar Díaz4James A. R. Dalton5James A. R. Dalton6James A. R. Dalton7Jesús Giraldo8Jesús Giraldo9Jesús Giraldo10Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, SpainBiophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia, Medellín, ColombiaLaboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, SpainUnitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, SpainInstituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, SpainLaboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, SpainUnitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, SpainInstituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, SpainLaboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, SpainUnitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, SpainInstituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, SpainAs a class C GPCR and regulator of synaptic activity, mGlu5 is an attractive drug target, potentially offering treatment for several neurologic and psychiatric disorders. As little is known about the activation mechanism of mGlu5 at a structural level, potential of mean force calculations linked to molecular dynamics simulations were performed on the mGlu5 transmembrane domain crystal structure to explore various internal mechanisms responsible for its activation. Our results suggest that the hydrophilic interactions between intracellular loop 1 and the intracellular side of TM6 have to be disrupted to reach a theoretically active-like conformation. In addition, interactions between residues that are key for mGlu5 activation (Tyr6593.44 and Ile7515.51) and mGlu5 inactivation (Tyr6593.44 and Ser8097.39) have been identified. Inasmuch as mGlu5 receptor signaling is poorly understood, potentially showing a complex network of micro-switches and subtle structure-activity relationships, the present study represents a step forward in the understanding of mGlu5 transmembrane domain activation.https://www.frontiersin.org/article/10.3389/fmolb.2020.00038/fullG protein-coupled receptorsmGlu5 receptormolecular dynamics computer simulationpotential of mean force calculationsfree energiesmGlu |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Isaias Lans Isaias Lans Óscar Díaz Óscar Díaz Óscar Díaz James A. R. Dalton James A. R. Dalton James A. R. Dalton Jesús Giraldo Jesús Giraldo Jesús Giraldo |
spellingShingle |
Isaias Lans Isaias Lans Óscar Díaz Óscar Díaz Óscar Díaz James A. R. Dalton James A. R. Dalton James A. R. Dalton Jesús Giraldo Jesús Giraldo Jesús Giraldo Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain Frontiers in Molecular Biosciences G protein-coupled receptors mGlu5 receptor molecular dynamics computer simulation potential of mean force calculations free energies mGlu |
author_facet |
Isaias Lans Isaias Lans Óscar Díaz Óscar Díaz Óscar Díaz James A. R. Dalton James A. R. Dalton James A. R. Dalton Jesús Giraldo Jesús Giraldo Jesús Giraldo |
author_sort |
Isaias Lans |
title |
Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain |
title_short |
Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain |
title_full |
Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain |
title_fullStr |
Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain |
title_full_unstemmed |
Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain |
title_sort |
exploring the activation mechanism of the mglu5 transmembrane domain |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Molecular Biosciences |
issn |
2296-889X |
publishDate |
2020-03-01 |
description |
As a class C GPCR and regulator of synaptic activity, mGlu5 is an attractive drug target, potentially offering treatment for several neurologic and psychiatric disorders. As little is known about the activation mechanism of mGlu5 at a structural level, potential of mean force calculations linked to molecular dynamics simulations were performed on the mGlu5 transmembrane domain crystal structure to explore various internal mechanisms responsible for its activation. Our results suggest that the hydrophilic interactions between intracellular loop 1 and the intracellular side of TM6 have to be disrupted to reach a theoretically active-like conformation. In addition, interactions between residues that are key for mGlu5 activation (Tyr6593.44 and Ile7515.51) and mGlu5 inactivation (Tyr6593.44 and Ser8097.39) have been identified. Inasmuch as mGlu5 receptor signaling is poorly understood, potentially showing a complex network of micro-switches and subtle structure-activity relationships, the present study represents a step forward in the understanding of mGlu5 transmembrane domain activation. |
topic |
G protein-coupled receptors mGlu5 receptor molecular dynamics computer simulation potential of mean force calculations free energies mGlu |
url |
https://www.frontiersin.org/article/10.3389/fmolb.2020.00038/full |
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