دورية أكاديمية
Shining Light On An mGlu5 Photoswitchable NAM : A Theoretical Perspective
| العنوان: | Shining Light On An mGlu5 Photoswitchable NAM : A Theoretical Perspective |
|---|---|
| المؤلفون: | Dalton, James A. R., Lans, Isaias, Rovira Algans, Xavier, Malhaire, Fanny, Gómez-Santacana, Xavier, Pittolo, Silvia, Gorostiza, Pau, Llebaria, Amadeu, Goudet, Cyril, Pin, Jean-Philippe, Giraldo, Jesús |
| سنة النشر: | 2016 |
| المجموعة: | Universitat Autònoma de Barcelona: Dipòsit Digital de Documents de la UAB |
| مصطلحات موضوعية: | Allosteric modulation, Docking, Metabotropic glutamate receptor, Molecular dynamics, Mutation, Protein structure, Transmembrane domain |
| الوصف: | 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) ; 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | Catalan; Valencian |
| ردمك: | 978-0-00-389450-9 0-00-389450-9 |
| تدمد: | 1570159X 18756190 |
| العلاقة: | 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; Current neuropharmacology; Vol. 14, Num. 5 (July 2016), p. 441-454; https://ddd.uab.cat/record/185421Test; urn:10.2174/1570159X13666150407231417; urn:PMC4983757; urn:oai:ddd.uab.cat:185421; urn:pmid:26391742; urn:recercauab:ARE-83111; urn:articleid:18756190v14n5p441; urn:scopus_id:84975690920; urn:wos_id:000389450900006; urn:oai:egreta.uab.cat:publications/d20d8696-6fca-41a1-90de-c82aee670f51; urn:pmc-uid:4983757; urn:pmcid:PMC4983757; urn:oai:pubmedcentral.nih.gov:4983757 |
| الإتاحة: | https://ddd.uab.cat/record/185421Test |
| حقوق: | open access ; Tots els drets reservats. ; https://rightsstatements.org/vocab/InC/1.0Test/ ; 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. ; https://creativecommons.org/licenses/by-nc/4.0Test/ |
| رقم الانضمام: | edsbas.3B6EA6C |
| قاعدة البيانات: | BASE |
Full Text Finder | ردمك: | 9780003894509 0003894509 |
|---|---|
| تدمد: | 1570159X 18756190 |