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Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities

γ-Aminobutyric acid type A (GABA(A)) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA(A))...

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Autores principales: Zhu, Shaotong, Sridhar, Akshay, Teng, Jinfeng, Howard, Rebecca J., Lindahl, Erik, Hibbs, Ryan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357065/
https://www.ncbi.nlm.nih.gov/pubmed/35933426
http://dx.doi.org/10.1038/s41467-022-32212-4
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author Zhu, Shaotong
Sridhar, Akshay
Teng, Jinfeng
Howard, Rebecca J.
Lindahl, Erik
Hibbs, Ryan E.
author_facet Zhu, Shaotong
Sridhar, Akshay
Teng, Jinfeng
Howard, Rebecca J.
Lindahl, Erik
Hibbs, Ryan E.
author_sort Zhu, Shaotong
collection PubMed
description γ-Aminobutyric acid type A (GABA(A)) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA(A)) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABA(A) receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at β/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABA(A) receptor allosteric modulators acting through a common site can have diverging activities.
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spelling pubmed-93570652022-08-08 Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities Zhu, Shaotong Sridhar, Akshay Teng, Jinfeng Howard, Rebecca J. Lindahl, Erik Hibbs, Ryan E. Nat Commun Article γ-Aminobutyric acid type A (GABA(A)) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA(A)) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABA(A) receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at β/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABA(A) receptor allosteric modulators acting through a common site can have diverging activities. Nature Publishing Group UK 2022-08-06 /pmc/articles/PMC9357065/ /pubmed/35933426 http://dx.doi.org/10.1038/s41467-022-32212-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhu, Shaotong
Sridhar, Akshay
Teng, Jinfeng
Howard, Rebecca J.
Lindahl, Erik
Hibbs, Ryan E.
Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities
title Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities
title_full Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities
title_fullStr Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities
title_full_unstemmed Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities
title_short Structural and dynamic mechanisms of GABA(A) receptor modulators with opposing activities
title_sort structural and dynamic mechanisms of gaba(a) receptor modulators with opposing activities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357065/
https://www.ncbi.nlm.nih.gov/pubmed/35933426
http://dx.doi.org/10.1038/s41467-022-32212-4
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