dc.contributor.author |
Dalton, James A. R.. |
dc.contributor.author |
Lans, Isaias |
dc.contributor.author |
Rovira Algans, Xavier |
dc.contributor.author |
Malhaire, Fanny |
dc.contributor.author |
Gómez-Santacana, Xavier |
dc.contributor.author |
Pittolo, Silvia |
dc.contributor.author |
Gorostiza, Pau |
dc.contributor.author |
Llebaria, Amadeu |
dc.contributor.author |
Goudet, Cyril |
dc.contributor.author |
Pin, Jean-Philippe |
dc.contributor.author |
Giraldo, Jesús |
dc.date |
2016 |
dc.identifier |
https://ddd.uab.cat/record/185421 |
dc.identifier |
urn:10.2174/1570159X13666150407231417 |
dc.identifier |
urn:PMC4983757 |
dc.identifier |
urn:oai:ddd.uab.cat:185421 |
dc.identifier |
urn:pmid:26391742 |
dc.identifier |
urn:recercauab:ARE-83111 |
dc.identifier |
urn:articleid:18756190v14n5p441 |
dc.identifier |
urn:scopus_id:84975690920 |
dc.identifier |
urn:wos_id:000389450900006 |
dc.identifier |
urn:oai:egreta.uab.cat:publications/d20d8696-6fca-41a1-90de-c82aee670f51 |
dc.identifier |
urn:pmc-uid:4983757 |
dc.identifier |
urn:pmcid:PMC4983757 |
dc.identifier |
urn:oai:pubmedcentral.nih.gov:4983757 |
dc.format |
application/pdf |
dc.format |
application/pdf |
dc.language |
cat |
dc.publisher |
|
dc.relation |
Ministerio de Economía y Competitividad SAF2010-19257 |
dc.relation |
Ministerio de Economía y Competitividad PCIN-2013-018-C03-02 |
dc.relation |
Agència de Gestió d'Ajuts Universitaris i de Recerca 2009SGR-1072 |
dc.relation |
Current neuropharmacology ; Vol. 14, Num. 5 (July 2016), p. 441-454 |
dc.rights |
open access |
dc.rights |
Tots els drets reservats. |
dc.rights |
https://rightsstatements.org/vocab/InC/1.0/ |
dc.rights |
open access |
dc.rights |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. |
dc.rights |
https://creativecommons.org/licenses/by-nc/4.0/ |
dc.subject |
Allosteric modulation |
dc.subject |
Docking |
dc.subject |
Metabotropic glutamate receptor |
dc.subject |
Molecular dynamics |
dc.subject |
Mutation |
dc.subject |
Protein structure |
dc.subject |
Transmembrane domain |
dc.title |
Shining Light On An mGlu5 Photoswitchable NAM : A Theoretical Perspective |
dc.type |
Article |
dc.description.abstract |
Altres ajuts: La Marató de TV3 (Refs. 110230, 110231 and 110232); European COST Action CM1207 (GLISTEN: GPCR.-Ligand Interactions, Structures, and Transmembrane Signalling: a European Research Network) |
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. |