Shining Light On An mGlu5 Photoswitchable NAM

Metabotropic glutamate receptors (mGluRs) are important drug targets because of their involvement in several neurological diseases. Among mGluRs, mGlu5 is a particularly high-profile target because its positive or negative allosteric modulation can potentially treat schizophrenia or anxiety and chro...

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Autores: Dalton, James A. R.|||0000-0002-5279-4581, Lans, Isaias|||0000-0002-9298-0346, Rovira Algans, Xavier, Malhaire, Fanny, Gómez-Santacana, Xavier|||0000-0001-8830-0494, Pittolo, Silvia|||0000-0002-5673-1692, Gorostiza, Pau|||0000-0002-7268-5577, Llebaria, Amadeu|||0000-0002-8200-4827, Goudet, Cyril|||0000-0002-8255-3535, Pin, Jean-Philippe|||0000-0002-1423-345X, Giraldo, Jesús|||0000-0001-7082-4695
Formato: artículo
Fecha de publicación:2016
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:catalán
OAI Identifier:oai:ddd.uab.cat:185421
Acesso em linha:https://ddd.uab.cat/record/185421
https://dx.doi.org/urn:doi:10.2174/1570159X13666150407231417
Access Level:acceso abierto
Palavra-chave:Allosteric modulation
Docking
Metabotropic glutamate receptor
Molecular dynamics
Mutation
Protein structure
Transmembrane domain
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spelling Shining Light On An mGlu5 Photoswitchable NAMA Theoretical PerspectiveDalton, James A. R.|||0000-0002-5279-4581Lans, Isaias|||0000-0002-9298-0346Rovira Algans, XavierMalhaire, FannyGómez-Santacana, Xavier|||0000-0001-8830-0494Pittolo, Silvia|||0000-0002-5673-1692Gorostiza, Pau|||0000-0002-7268-5577Llebaria, Amadeu|||0000-0002-8200-4827Goudet, Cyril|||0000-0002-8255-3535Pin, Jean-Philippe|||0000-0002-1423-345XGiraldo, Jesús|||0000-0001-7082-4695Allosteric modulationDockingMetabotropic glutamate receptorMolecular dynamicsMutationProtein structureTransmembrane domainMetabotropic glutamate receptors (mGluRs) are important drug targets because of their involvement in several neurological diseases. Among mGluRs, mGlu5 is a particularly high-profile target because its positive or negative allosteric modulation can potentially treat schizophrenia or anxiety and chronic pain, respectively. Here, we computationally and experimentally probe the functional binding of a novel photoswitchable mGlu5 NAM, termed alloswitch-1, which loses its NAM functionality under violet light. We show alloswitch-1 binds deep in the allosteric pocket in a similar fashion to mavoglurant, the co-crystallized NAM in the mGlu5 transmembrane domain crystal structure. Alloswitch-1, like NAM 2-Methyl-6-(phenylethynyl)pyridine (MPEP), is significantly affected by P655M mutation deep in the allosteric pocket, eradicating its functionality. In MD simulations, we show alloswitch-1 and MPEP stabilize the co-crystallized water molecule located at the bottom of the allosteric site that is seemingly characteristic of the inactive receptor state. Furthermore, both NAMs form H-bonds with S809 on helix 7, which may constitute an important stabilizing interaction for NAM-induced mGlu5 inactivation. Alloswitch-1, through isomerization of its amide group from trans to cis is able to form an additional interaction with N747 on helix 5. This may be an important interaction for amide-containing mGlu5 NAMs, helping to stabilize their binding in a potentially unusual cis-amide state. Simulated conformational switching of alloswitch-1 in silico suggests photoisomerization of its azo group from trans to cis may be possible within the allosteric pocket. However, photoexcited alloswitch-1 binds in an unstable fashion, breaking H-bonds with the protein and destabilizing the co-crystallized water molecule. This suggests photoswitching may have destabilizing effects on mGlu5 binding and functionality. 22016-01-0120162016-01-01Articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/185421https://dx.doi.org/urn:doi:10.2174/1570159X13666150407231417reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaCataláncatMinisterio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2010-19257Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PCIN-2013-018-C03-02Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2009/SGR-1072open accesshttp://purl.org/coar/access_right/c_abf2Aquest material està protegit per drets d'autor i/o drets afins. Podeu utilitzar aquest material en funció del que permet la legislació de drets d'autor i drets afins d'aplicació al vostre cas. Per a d'altres usos heu d'obtenir permís del(s) titular(s) de drets.https://rightsstatements.org/vocab/InC/1.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:1854212026-06-06T12:50:31Z
dc.title.none.fl_str_mv Shining Light On An mGlu5 Photoswitchable NAM
A Theoretical Perspective
title Shining Light On An mGlu5 Photoswitchable NAM
spellingShingle Shining Light On An mGlu5 Photoswitchable NAM
Dalton, James A. R.|||0000-0002-5279-4581
Allosteric modulation
Docking
Metabotropic glutamate receptor
Molecular dynamics
Mutation
Protein structure
Transmembrane domain
title_short Shining Light On An mGlu5 Photoswitchable NAM
title_full Shining Light On An mGlu5 Photoswitchable NAM
title_fullStr Shining Light On An mGlu5 Photoswitchable NAM
title_full_unstemmed Shining Light On An mGlu5 Photoswitchable NAM
title_sort Shining Light On An mGlu5 Photoswitchable NAM
dc.creator.none.fl_str_mv Dalton, James A. R.|||0000-0002-5279-4581
Lans, Isaias|||0000-0002-9298-0346
Rovira Algans, Xavier
Malhaire, Fanny
Gómez-Santacana, Xavier|||0000-0001-8830-0494
Pittolo, Silvia|||0000-0002-5673-1692
Gorostiza, Pau|||0000-0002-7268-5577
Llebaria, Amadeu|||0000-0002-8200-4827
Goudet, Cyril|||0000-0002-8255-3535
Pin, Jean-Philippe|||0000-0002-1423-345X
Giraldo, Jesús|||0000-0001-7082-4695
author Dalton, James A. R.|||0000-0002-5279-4581
author_facet Dalton, James A. R.|||0000-0002-5279-4581
Lans, Isaias|||0000-0002-9298-0346
Rovira Algans, Xavier
Malhaire, Fanny
Gómez-Santacana, Xavier|||0000-0001-8830-0494
Pittolo, Silvia|||0000-0002-5673-1692
Gorostiza, Pau|||0000-0002-7268-5577
Llebaria, Amadeu|||0000-0002-8200-4827
Goudet, Cyril|||0000-0002-8255-3535
Pin, Jean-Philippe|||0000-0002-1423-345X
Giraldo, Jesús|||0000-0001-7082-4695
author_role author
author2 Lans, Isaias|||0000-0002-9298-0346
Rovira Algans, Xavier
Malhaire, Fanny
Gómez-Santacana, Xavier|||0000-0001-8830-0494
Pittolo, Silvia|||0000-0002-5673-1692
Gorostiza, Pau|||0000-0002-7268-5577
Llebaria, Amadeu|||0000-0002-8200-4827
Goudet, Cyril|||0000-0002-8255-3535
Pin, Jean-Philippe|||0000-0002-1423-345X
Giraldo, Jesús|||0000-0001-7082-4695
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Allosteric modulation
Docking
Metabotropic glutamate receptor
Molecular dynamics
Mutation
Protein structure
Transmembrane domain
topic Allosteric modulation
Docking
Metabotropic glutamate receptor
Molecular dynamics
Mutation
Protein structure
Transmembrane domain
description Metabotropic glutamate receptors (mGluRs) are important drug targets because of their involvement in several neurological diseases. Among mGluRs, mGlu5 is a particularly high-profile target because its positive or negative allosteric modulation can potentially treat schizophrenia or anxiety and chronic pain, respectively. Here, we computationally and experimentally probe the functional binding of a novel photoswitchable mGlu5 NAM, termed alloswitch-1, which loses its NAM functionality under violet light. We show alloswitch-1 binds deep in the allosteric pocket in a similar fashion to mavoglurant, the co-crystallized NAM in the mGlu5 transmembrane domain crystal structure. Alloswitch-1, like NAM 2-Methyl-6-(phenylethynyl)pyridine (MPEP), is significantly affected by P655M mutation deep in the allosteric pocket, eradicating its functionality. In MD simulations, we show alloswitch-1 and MPEP stabilize the co-crystallized water molecule located at the bottom of the allosteric site that is seemingly characteristic of the inactive receptor state. Furthermore, both NAMs form H-bonds with S809 on helix 7, which may constitute an important stabilizing interaction for NAM-induced mGlu5 inactivation. Alloswitch-1, through isomerization of its amide group from trans to cis is able to form an additional interaction with N747 on helix 5. This may be an important interaction for amide-containing mGlu5 NAMs, helping to stabilize their binding in a potentially unusual cis-amide state. Simulated conformational switching of alloswitch-1 in silico suggests photoisomerization of its azo group from trans to cis may be possible within the allosteric pocket. However, photoexcited alloswitch-1 binds in an unstable fashion, breaking H-bonds with the protein and destabilizing the co-crystallized water molecule. This suggests photoswitching may have destabilizing effects on mGlu5 binding and functionality.
publishDate 2016
dc.date.none.fl_str_mv 2
2016-01-01
2016
2016-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/185421
https://dx.doi.org/urn:doi:10.2174/1570159X13666150407231417
url https://ddd.uab.cat/record/185421
https://dx.doi.org/urn:doi:10.2174/1570159X13666150407231417
dc.language.none.fl_str_mv Catalán
cat
language_invalid_str_mv Catalán
language cat
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2010-19257
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PCIN-2013-018-C03-02
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2009/SGR-1072
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://rightsstatements.org/vocab/InC/1.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://rightsstatements.org/vocab/InC/1.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
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repository.mail.fl_str_mv
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