Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand

Abstract As class C GPCRs and regulators of synaptic activity, human metabotropic glutamate receptors (mGluRs) 4 and 5 are prime targets for allosteric modulation, with mGlu5 inhibition or mGlu4 stimulation potentially treating conditions like chronic pain and Parkinson’s disease. As an allosteric m...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	James A. R. Dalton, Jean-Philippe Pin, Jesús Giraldo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dc6b6cc3d3da4edda972deaf48dffd16
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:dc6b6cc3d3da4edda972deaf48dffd16
record_format	dspace
spelling	oai:doaj.org-article:dc6b6cc3d3da4edda972deaf48dffd162021-12-02T11:53:00ZAnalysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand10.1038/s41598-017-05095-52045-2322https://doaj.org/article/dc6b6cc3d3da4edda972deaf48dffd162017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05095-5https://doaj.org/toc/2045-2322Abstract As class C GPCRs and regulators of synaptic activity, human metabotropic glutamate receptors (mGluRs) 4 and 5 are prime targets for allosteric modulation, with mGlu5 inhibition or mGlu4 stimulation potentially treating conditions like chronic pain and Parkinson’s disease. As an allosteric modulator that can bind both receptors, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) is able to negatively modulate mGlu5 or positively modulate mGlu4. At a structural level, how it elicits these responses and how mGluRs undergo activation is unclear. Here, we employ homology modelling and 30 µs of atomistic molecular dynamics (MD) simulations to probe allosteric conformational change in mGlu4 and mGlu5, with and without docked MPEP. Our results identify several structural differences between mGlu4 and mGlu5, as well as key differences responsible for MPEP-mediated positive and negative allosteric modulation, respectively. A novel mechanism of mGlu4 activation is revealed, which may apply to all mGluRs in general. This involves conformational changes in TM3, TM4 and TM5, separation of intracellular loop 2 (ICL2) from ICL1/ICL3, and destabilization of the ionic-lock. On the other hand, mGlu5 experiences little disturbance when MPEP binds, maintaining its inactive state with reduced conformational fluctuation. In addition, when MPEP is absent, a lipid molecule can enter the mGlu5 allosteric pocket.James A. R. DaltonJean-Philippe PinJesús GiraldoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q James A. R. Dalton Jean-Philippe Pin Jesús Giraldo Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
description	Abstract As class C GPCRs and regulators of synaptic activity, human metabotropic glutamate receptors (mGluRs) 4 and 5 are prime targets for allosteric modulation, with mGlu5 inhibition or mGlu4 stimulation potentially treating conditions like chronic pain and Parkinson’s disease. As an allosteric modulator that can bind both receptors, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) is able to negatively modulate mGlu5 or positively modulate mGlu4. At a structural level, how it elicits these responses and how mGluRs undergo activation is unclear. Here, we employ homology modelling and 30 µs of atomistic molecular dynamics (MD) simulations to probe allosteric conformational change in mGlu4 and mGlu5, with and without docked MPEP. Our results identify several structural differences between mGlu4 and mGlu5, as well as key differences responsible for MPEP-mediated positive and negative allosteric modulation, respectively. A novel mechanism of mGlu4 activation is revealed, which may apply to all mGluRs in general. This involves conformational changes in TM3, TM4 and TM5, separation of intracellular loop 2 (ICL2) from ICL1/ICL3, and destabilization of the ionic-lock. On the other hand, mGlu5 experiences little disturbance when MPEP binds, maintaining its inactive state with reduced conformational fluctuation. In addition, when MPEP is absent, a lipid molecule can enter the mGlu5 allosteric pocket.
format	article
author	James A. R. Dalton Jean-Philippe Pin Jesús Giraldo
author_facet	James A. R. Dalton Jean-Philippe Pin Jesús Giraldo
author_sort	James A. R. Dalton
title	Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
title_short	Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
title_full	Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
title_fullStr	Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
title_full_unstemmed	Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
title_sort	analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/dc6b6cc3d3da4edda972deaf48dffd16
work_keys_str_mv	AT jamesardalton analysisofpositiveandnegativeallostericmodulationinmetabotropicglutamatereceptors4and5withadualligand AT jeanphilippepin analysisofpositiveandnegativeallostericmodulationinmetabotropicglutamatereceptors4and5withadualligand AT jesusgiraldo analysisofpositiveandnegativeallostericmodulationinmetabotropicglutamatereceptors4and5withadualligand
_version_	1718394956282855424

Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand

Ejemplares similares