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| Pàgina inicial > Articles > Articles publicats > Shining Light On An mGlu5 Photoswitchable NAM : |
(Universitat Autònoma de Barcelona. Institut de Neurociències) (Universitat Autònoma de Barcelona. Institut de Neurociències) (Universitat Autònoma de Barcelona. Institut de Neurociències) (Institut de Bioenginyeria de Catalunya) (Institut de Bioenginyeria de Catalunya) (Institut de Química Avançada de Catalunya) (Institut de Génomique Fonctionnelle) (Institut de Génomique Fonctionnelle) (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. |
| Ajuts: | Ministerio de Economía y Competitividad SAF2010-19257 Ministerio de Economía y Competitividad PCIN-2013-018-C03-02 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009SGR-1072 |
| 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) |
| 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.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió acceptada per publicar |
| 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 1875-6190 |
Tots els drets reservats 24 p, 1.3 MB |
14 p, 23.8 MB |
