dc.contributor.author |
Dalton, James A. R. |
dc.contributor.author |
Lans, Isaias |
dc.contributor.author |
Rovira, Xavier |
dc.contributor.author |
Malhaire, Fanny |
dc.contributor.author |
Gómez Santacana, Xavier |
dc.contributor.author |
Pittolo, Silvia |
dc.contributor.author |
Gorostiza Langa, Pablo Ignacio |
dc.contributor.author |
Llebaria Soldevila, Amadeu |
dc.contributor.author |
Goudet, Cyril |
dc.contributor.author |
Pin, Jean-Philippe |
dc.contributor.author |
Giraldo, Jesús |
dc.date |
2017-09-19T10:50:05Z |
dc.date |
2017-09-19T10:50:05Z |
dc.date |
2016-05-01 |
dc.identifier.citation |
1570-159X |
dc.identifier.uri |
http://hdl.handle.net/2445/115606 |
dc.format |
14 p. |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
Bentham Science |
dc.relation |
Reproducció del document publicat a: http://dx.doi.org/10.2174/1570159X13666150407231417 |
dc.relation |
Current Neuropharmacology, 2016, vol. 14, num. 5, p. 441-454 |
dc.relation |
http://dx.doi.org/10.2174/1570159X13666150407231417 |
dc.rights |
(c) Bentham Science, 2015 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.title |
Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/acceptedVersion |
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. |