Home > Articles > Published articles > Shining Light On An mGlu5 Photoswitchable NAM : |
Date: | 2016 |
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. |
Grants: | 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 |
Note: | 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) |
Rights: | Tots els drets reservats. |
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. |
Language: | Anglès |
Document: | Article ; recerca ; Versió acceptada per publicar |
Subject: | Allosteric modulation ; Docking ; Metabotropic glutamate receptor ; Molecular dynamics ; Mutation ; Protein structure ; Transmembrane domain |
Published in: | Current neuropharmacology, Vol. 14, Num. 5 (July 2016) , p. 441-454, ISSN 1875-6190 |
Postprint Tots els drets reservats 24 p, 1.3 MB |
CC-BY-NC 14 p, 23.8 MB |