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dc.contributor.authorFreyd, Thibaud
dc.contributor.authorWarszycki, Dawid
dc.contributor.authorMordalski, Stefan
dc.contributor.authorBojarski, Andrzej J
dc.contributor.authorSylte, Ingebrigt
dc.contributor.authorGabrielsen, Mari
dc.date.accessioned2018-03-06T10:20:43Z
dc.date.available2018-03-06T10:20:43Z
dc.date.issued2017-03-21
dc.description.abstractγ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and disturbances in the GABAergic system have been implicated in numerous neurological and neuropsychiatric diseases. The GABA<sub>B</sub> receptor is a heterodimeric class C G protein-coupled receptor (GPCR) consisting of GABA<sub>B1a/b</sub> and GABA<sub>B2</sub> subunits. Two GABA<sub>B</sub> receptor ligand binding sites have been described, namely the orthosteric GABA binding site located in the extracellular GABA<sub>B1</sub> Venus fly trap domain and the allosteric binding site found in the GABA<sub>B2</sub> transmembrane domain. To date, the only experimentally solved three-dimensional structures of the GABA<sub>B</sub> receptor are of the Venus fly trap domain. GABA<sub>B</sub>receptor allosteric modulators, however, show great therapeutic potential, and elucidating the structure of the GABA<sub>B2</sub> transmembrane domain may lead to development of novel drugs and increased understanding of the allosteric mechanism of action. Despite the lack of x-ray crystal structures of the GABA<sub>B2</sub> transmembrane domain, multiple crystal structures belonging to other classes of GPCRs than class A have been released within the last years. More closely related template structures are now available for homology modelling of the GABA<sub>B</sub> receptor. Here, multiple homology models of the GABA<sub>B2</sub> subunit of the GABA<sub>B</sub> receptor have been constructed using templates from class A, B and C GPCRs, and docking of five clusters of positive allosteric modulators and decoys has been undertaken to select models that enrich the active compounds. Using this ligand-guided approach, eight GABA<sub>B2</sub> homology models have been chosen as possible structural representatives of the transmembrane domain of the GABA<sub>B2</sub> subunit. To the best of our knowledge, the present study is the first to describe homology modelling of the transmembrane domain of the GABA<sub>B2</sub> subunit and the docking of positive allosteric modulators in the receptor.en_US
dc.description.sponsorshipPolish-Norwegian Research Program, Pol-Nor/198887/73/2013en_US
dc.descriptionSource at <a href=https://doi.org/10.1371/journal.pone.0173889>https://doi.org/10.1371/journal.pone.0173889 </a>.en_US
dc.identifier.citationFreyd, T., Warszycki, D., Mordalski, S., Bojarski, A. J., Sylte, I. S. & Gabrielsen, M. (2017). Ligand-guided homology modelling of the GABAb2 subunit of the GABAb receptor. PLoS ONE. 12(3). https://doi.org/10.1371/journal.pone.0173889en_US
dc.identifier.cristinIDFRIDAID 1508215
dc.identifier.doi10.1371/journal.pone.0173889
dc.identifier.issn1932-6203
dc.identifier.urihttps://hdl.handle.net/10037/12257
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.ispartofFreyd, T. (2018). Allosteric modulation of GABAergic and glutamatergic metabotropic receptors. Doctoral thesis. <a href=http://hdl.handle.net/10037/13978>http://hdl.handle.net/10037/13978.</a>
dc.relation.journalPLoS ONE
dc.relation.projectIDNotur/NorStore: NN2978Ken_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical molecular biology: 711en_US
dc.titleLigand-guided homology modelling of the GABAb2 subunit of the GABAb receptoren_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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