Structures of KcsA in complex with symmetrical quaternary ammonium compounds reveal a hydrophobic binding site

Michael J. Lenaeus, Dylan Burdette, Tobias Wagner, Pamela J Focia, Adrian Gross*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5365-5373
Number of pages9
JournalBiochemistry
Volume53
Issue number32
DOIs
StatePublished - Aug 19 2014

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Quaternary Ammonium Compounds
Potassium Channels
Binding Sites
Membranes
Sodium Channels
Cell membranes
Ammonium Compounds
Membrane Potentials
Structural properties
Potassium
Cell Membrane
Ions
Molecules
Pharmaceutical Preparations
prokaryotic potassium channel

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. In: Biochemistry. 2014 ; Vol. 53, No. 32. pp. 5365-5373.
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abstract = "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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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.

In: Biochemistry, Vol. 53, No. 32, 19.08.2014, p. 5365-5373.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structures of KcsA in complex with symmetrical quaternary ammonium compounds reveal a hydrophobic binding site

AU - Lenaeus, Michael J.

AU - Burdette, Dylan

AU - Wagner, Tobias

AU - Focia, Pamela J

AU - Gross, Adrian

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AB - 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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