Web of Science: 10 cites, Scopus: 8 cites, Google Scholar: cites
Shining Light On An mGlu5 Photoswitchable NAM : A Theoretical Perspective
Dalton, James A.R. (Universitat Autònoma de Barcelona. Institut de Neurociències)
Lans, Isaias (Universitat Autònoma de Barcelona. Institut de Neurociències)
Rovira Algans, Xavier (Institut de Génomique Fonctionnelle)
Malhaire, Fanny (Institut de Génomique Fonctionnelle)
Gómez-Santacana, Xavier (Universitat Autònoma de Barcelona. Institut de Neurociències)
Pittolo, Silvia (Institute for Bioengineering of Catalonia (IBEC))
Gorostiza, Pau (Institute for Bioengineering of Catalonia (IBEC))
Llebaria, Amadeu (Institut de Química Avançada de Catalunya)
Goudet, Cyril (Institut de Génomique Fonctionnelle)
Pin, Jean-Philippe (Institut de Génomique Fonctionnelle)
Giraldo, Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)

Data: 2016
Resum: 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.
Nota: 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)
Nota: Número d'acord de subvenció MINECO/SAF2010-19257
Nota: Número d'acord de subvenció MINECO/PCIN-2013-018-C03-02
Nota: Número d'acord de subvenció AGAUR/2009SGR-1072
Drets: Tots els drets reservats
Drets: 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. Creative Commons
Llengua: Anglès.
Document: article ; recerca ; acceptedVersion ; publishedVersion
Matèria: Allosteric modulation ; Docking ; Metabotropic glutamate receptor ; Molecular dynamics ; Mutation ; Protein structure ; Transmembrane domain
Publicat a: Current Neuropharmacology, Vol. 14, Num. 5 (July 2016) , p. 441-454, ISSN 1570-159X

DOI: 10.2174/1570159X13666150407231417
PMID: 26391742

Tots els drets reservats
24 p, 1.3 MB

14 p, 23.8 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Neurociències (INc)
Articles > Articles de recerca
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 Registre creat el 2018-01-31, darrera modificació el 2020-08-03

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