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A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

We present a full-length α(1)β(2)γ(2) GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutam...

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Detalles Bibliográficos
Autores principales: Bergmann, Rikke, Kongsbak, Kristine, Sørensen, Pernille Louise, Sander, Tommy, Balle, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538749/
https://www.ncbi.nlm.nih.gov/pubmed/23308109
http://dx.doi.org/10.1371/journal.pone.0052323
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author Bergmann, Rikke
Kongsbak, Kristine
Sørensen, Pernille Louise
Sander, Tommy
Balle, Thomas
author_facet Bergmann, Rikke
Kongsbak, Kristine
Sørensen, Pernille Louise
Sander, Tommy
Balle, Thomas
author_sort Bergmann, Rikke
collection PubMed
description We present a full-length α(1)β(2)γ(2) GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and the backbone of β(2)S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and β(2)F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β(2)S156 and β(2)Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α(1)T206 and γ(2)T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α(1)H101 and the N-methyl group near α(1)Y159, α(1)T206, and α(1)Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABA(A) receptor is made available as Model S1.
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spelling pubmed-35387492013-01-10 A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites Bergmann, Rikke Kongsbak, Kristine Sørensen, Pernille Louise Sander, Tommy Balle, Thomas PLoS One Research Article We present a full-length α(1)β(2)γ(2) GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and the backbone of β(2)S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and β(2)F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β(2)S156 and β(2)Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α(1)T206 and γ(2)T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α(1)H101 and the N-methyl group near α(1)Y159, α(1)T206, and α(1)Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABA(A) receptor is made available as Model S1. Public Library of Science 2013-01-07 /pmc/articles/PMC3538749/ /pubmed/23308109 http://dx.doi.org/10.1371/journal.pone.0052323 Text en © 2013 Bergmann et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bergmann, Rikke
Kongsbak, Kristine
Sørensen, Pernille Louise
Sander, Tommy
Balle, Thomas
A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites
title A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites
title_full A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites
title_fullStr A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites
title_full_unstemmed A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites
title_short A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites
title_sort unified model of the gaba(a) receptor comprising agonist and benzodiazepine binding sites
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538749/
https://www.ncbi.nlm.nih.gov/pubmed/23308109
http://dx.doi.org/10.1371/journal.pone.0052323
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