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Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site

[Image: see text] Potassium channels allow for the passive movement of potassium ions across the cell membrane and are instrumental in controlling the membrane potential in all cell types. Quaternary ammonium (QA) compounds block potassium channels and have long been used to study the functional and...

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Autores principales: Lenaeus, Michael J., Burdette, Dylan, Wagner, Tobias, Focia, Pamela J., Gross, Adrian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139162/
https://www.ncbi.nlm.nih.gov/pubmed/25093676
http://dx.doi.org/10.1021/bi500525s
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author Lenaeus, Michael J.
Burdette, Dylan
Wagner, Tobias
Focia, Pamela J.
Gross, Adrian
author_facet Lenaeus, Michael J.
Burdette, Dylan
Wagner, Tobias
Focia, Pamela J.
Gross, Adrian
author_sort Lenaeus, Michael J.
collection PubMed
description [Image: see text] Potassium channels allow for the passive movement of potassium ions across the cell membrane and are instrumental in controlling the membrane potential in all cell types. Quaternary ammonium (QA) compounds block potassium channels and have long been used to study the functional and structural properties of these channels. Here we describe the interaction between three symmetrical hydrophobic QAs and the prokaryotic potassium channel KcsA. The structures demonstrate the presence of a hydrophobic pocket between the inner helices of KcsA and provide insight into the binding site and blocking mechanism of hydrophobic QAs. The structures also reveal a structurally hidden pathway between the central cavity and the outside membrane environment reminiscent of the lateral fenestration observed in sodium channels that can be accessed through small conformational changes in the pore wall. We propose that the hydrophobic binding pocket stabilizes the alkyl chains of long-chain QA molecules and may play a key role in hydrophobic drug binding in general.
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spelling pubmed-41391622015-08-05 Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site Lenaeus, Michael J. Burdette, Dylan Wagner, Tobias Focia, Pamela J. Gross, Adrian Biochemistry [Image: see text] Potassium channels allow for the passive movement of potassium ions across the cell membrane and are instrumental in controlling the membrane potential in all cell types. Quaternary ammonium (QA) compounds block potassium channels and have long been used to study the functional and structural properties of these channels. Here we describe the interaction between three symmetrical hydrophobic QAs and the prokaryotic potassium channel KcsA. The structures demonstrate the presence of a hydrophobic pocket between the inner helices of KcsA and provide insight into the binding site and blocking mechanism of hydrophobic QAs. The structures also reveal a structurally hidden pathway between the central cavity and the outside membrane environment reminiscent of the lateral fenestration observed in sodium channels that can be accessed through small conformational changes in the pore wall. We propose that the hydrophobic binding pocket stabilizes the alkyl chains of long-chain QA molecules and may play a key role in hydrophobic drug binding in general. American Chemical Society 2014-08-05 2014-08-19 /pmc/articles/PMC4139162/ /pubmed/25093676 http://dx.doi.org/10.1021/bi500525s Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Lenaeus, Michael J.
Burdette, Dylan
Wagner, Tobias
Focia, Pamela J.
Gross, Adrian
Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site
title Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site
title_full Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site
title_fullStr Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site
title_full_unstemmed Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site
title_short Structures of KcsA in Complex with Symmetrical Quaternary Ammonium Compounds Reveal a Hydrophobic Binding Site
title_sort structures of kcsa in complex with symmetrical quaternary ammonium compounds reveal a hydrophobic binding site
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139162/
https://www.ncbi.nlm.nih.gov/pubmed/25093676
http://dx.doi.org/10.1021/bi500525s
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