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Title: | Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective |
Author: | Dalton, James A. R. Lans, Isaias Rovira, Xavier Malhaire, Fanny Gómez Santacana, Xavier Pittolo, Silvia Gorostiza Langa, Pablo Ignacio Llebaria Soldevila, Amadeu Goudet, Cyril Pin, Jean-Philippe Giraldo, Jesús |
Keywords: | Dinàmica molecular Proteïnes Molecular dynamics Proteins |
Issue Date: | 1-May-2016 |
Publisher: | Bentham Science |
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. |
Note: | Reproducció del document publicat a: http://dx.doi.org/10.2174/1570159X13666150407231417 |
It is part of: | Current Neuropharmacology, 2016, vol. 14, num. 5, p. 441-454 |
URI: | http://hdl.handle.net/2445/115606 |
Related resource: | http://dx.doi.org/10.2174/1570159X13666150407231417 |
ISSN: | 1570-159X |
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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