Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective

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., Lans, Isaias, Rovira, Xavier, Malhaire, Fanny, Gómez Santacana, Xavier, Pittolo, Silvia, Gorostiza Langa, Pablo Ignacio, Llebaria Soldevila, Amadeu, Goudet, Cyril, Pin, Jean-Philippe, Giraldo, Jesús
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2016
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/115606
Acceso en línea:https://hdl.handle.net/2445/115606
Access Level:acceso abierto
Palabra clave:Dinàmica molecular
Proteïnes
Molecular dynamics
Proteins
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spelling Shining light on an mGlu5 photoswitchable NAM: A theoretical perspectiveDalton, James A. R.Lans, IsaiasRovira, XavierMalhaire, FannyGómez Santacana, XavierPittolo, SilviaGorostiza Langa, Pablo IgnacioLlebaria Soldevila, AmadeuGoudet, CyrilPin, Jean-PhilippeGiraldo, JesúsDinàmica molecularProteïnesMolecular dynamicsProteinsMetabotropic 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.Bentham Science2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/115606Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: http://dx.doi.org/10.2174/1570159X13666150407231417Current Neuropharmacology, 2016, vol. 14, num. 5, p. 441-454http://dx.doi.org/10.2174/1570159X13666150407231417info:eu-repo/grantAgreement/EC/H2020/720270(c) Bentham Science, 2015info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1156062026-05-27T06:46:51Z
dc.title.none.fl_str_mv Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
title Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
spellingShingle Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
Dalton, James A. R.
Dinàmica molecular
Proteïnes
Molecular dynamics
Proteins
title_short Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
title_full Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
title_fullStr Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
title_full_unstemmed Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
title_sort Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective
dc.creator.none.fl_str_mv Dalton, James A. R.
Lans, Isaias
Rovira, Xavier
Malhaire, Fanny
Gómez Santacana, Xavier
Pittolo, Silvia
Gorostiza Langa, Pablo Ignacio
Llebaria Soldevila, Amadeu
Goudet, Cyril
Pin, Jean-Philippe
Giraldo, Jesús
author Dalton, James A. R.
author_facet Dalton, James A. R.
Lans, Isaias
Rovira, Xavier
Malhaire, Fanny
Gómez Santacana, Xavier
Pittolo, Silvia
Gorostiza Langa, Pablo Ignacio
Llebaria Soldevila, Amadeu
Goudet, Cyril
Pin, Jean-Philippe
Giraldo, Jesús
author_role author
author2 Lans, Isaias
Rovira, Xavier
Malhaire, Fanny
Gómez Santacana, Xavier
Pittolo, Silvia
Gorostiza Langa, Pablo Ignacio
Llebaria Soldevila, Amadeu
Goudet, Cyril
Pin, Jean-Philippe
Giraldo, Jesús
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dinàmica molecular
Proteïnes
Molecular dynamics
Proteins
topic Dinàmica molecular
Proteïnes
Molecular dynamics
Proteins
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 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/115606
url https://hdl.handle.net/2445/115606
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.2174/1570159X13666150407231417
Current Neuropharmacology, 2016, vol. 14, num. 5, p. 441-454
http://dx.doi.org/10.2174/1570159X13666150407231417
info:eu-repo/grantAgreement/EC/H2020/720270
dc.rights.none.fl_str_mv (c) Bentham Science, 2015
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Bentham Science, 2015
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Bentham Science
publisher.none.fl_str_mv Bentham Science
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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