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http://hdl.handle.net/2445/115606
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DC Field | Value | Language |
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dc.contributor.author | Dalton, James A. R. | - |
dc.contributor.author | Lans, Isaias | - |
dc.contributor.author | Rovira, Xavier | - |
dc.contributor.author | Malhaire, Fanny | - |
dc.contributor.author | Gómez Santacana, Xavier | - |
dc.contributor.author | Pittolo, Silvia | - |
dc.contributor.author | Gorostiza Langa, Pablo Ignacio | - |
dc.contributor.author | Llebaria Soldevila, Amadeu | - |
dc.contributor.author | Goudet, Cyril | - |
dc.contributor.author | Pin, Jean-Philippe | - |
dc.contributor.author | Giraldo, Jesús | - |
dc.date.accessioned | 2017-09-19T10:50:05Z | - |
dc.date.available | 2017-09-19T10:50:05Z | - |
dc.date.issued | 2016-05-01 | - |
dc.identifier.issn | 1570-159X | - |
dc.identifier.uri | http://hdl.handle.net/2445/115606 | - |
dc.description.abstract | 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. | ca |
dc.format.extent | 14 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | ca |
dc.publisher | Bentham Science | ca |
dc.relation.isformatof | Reproducció del document publicat a: http://dx.doi.org/10.2174/1570159X13666150407231417 | - |
dc.relation.ispartof | Current Neuropharmacology, 2016, vol. 14, num. 5, p. 441-454 | - |
dc.relation.uri | http://dx.doi.org/10.2174/1570159X13666150407231417 | - |
dc.rights | (c) Bentham Science, 2015 | - |
dc.source | Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC)) | - |
dc.subject.classification | Dinàmica molecular | - |
dc.subject.classification | Proteïnes | - |
dc.subject.other | Molecular dynamics | - |
dc.subject.other | Proteins | - |
dc.title | Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective | ca |
dc.type | info:eu-repo/semantics/article | ca |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/720270/EU//HBP SGA1 | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca |
dc.identifier.pmid | 26391742 | - |
Appears in Collections: | Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC)) Publicacions de projectes de recerca finançats per la UE |
Files in This Item:
File | Description | Size | Format | |
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L01_2016_Current Neuropharmacology_14_441_OA.pdf | 881.87 kB | Adobe PDF | View/Open |
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