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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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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. |
format | Online Article Text |
id | pubmed-3538749 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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