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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Bentham Science Publishers
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983757/ https://www.ncbi.nlm.nih.gov/pubmed/26391742 http://dx.doi.org/10.2174/1570159X13666150407231417 |
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author | Dalton, James A.R. Lans, Isaias Rovira, Xavier Malhaire, Fanny Gómez-Santacana, Xavier Pittolo, Silvia Gorostiza, Pau Llebaria, Amadeu Goudet, Cyril Pin, Jean-Philippe Giraldo, Jesús |
author_facet | Dalton, James A.R. Lans, Isaias Rovira, Xavier Malhaire, Fanny Gómez-Santacana, Xavier Pittolo, Silvia Gorostiza, Pau Llebaria, Amadeu Goudet, Cyril Pin, Jean-Philippe Giraldo, Jesús |
author_sort | Dalton, James A.R. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-4983757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Bentham Science Publishers |
record_format | MEDLINE/PubMed |
spelling | pubmed-49837572017-01-01 Shining Light on an mGlu5 Photoswitchable NAM: A Theoretical Perspective Dalton, James A.R. Lans, Isaias Rovira, Xavier Malhaire, Fanny Gómez-Santacana, Xavier Pittolo, Silvia Gorostiza, Pau Llebaria, Amadeu Goudet, Cyril Pin, Jean-Philippe Giraldo, Jesús Curr Neuropharmacol Article 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. Bentham Science Publishers 2016-07 2016-07 /pmc/articles/PMC4983757/ /pubmed/26391742 http://dx.doi.org/10.2174/1570159X13666150407231417 Text en © 2016 Bentham Science Publishers https://creativecommons.org/licenses/by-nc/4.0/legalcode This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. |
spellingShingle | Article Dalton, James A.R. Lans, Isaias Rovira, Xavier Malhaire, Fanny Gómez-Santacana, Xavier Pittolo, Silvia Gorostiza, Pau Llebaria, Amadeu Goudet, Cyril Pin, Jean-Philippe Giraldo, Jesús Shining Light on an mGlu5 Photoswitchable NAM: A Theoretical Perspective |
title | 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_short | Shining Light on an mGlu5 Photoswitchable NAM: A Theoretical Perspective |
title_sort | shining light on an mglu5 photoswitchable nam: a theoretical perspective |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983757/ https://www.ncbi.nlm.nih.gov/pubmed/26391742 http://dx.doi.org/10.2174/1570159X13666150407231417 |
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