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Molecular modeling of a tandem two pore domain potassium channel reveals a putative binding site for general anesthetics.

Authors
  • Bertaccini, Edward J1
  • Dickinson, Robert
  • Trudell, James R
  • Franks, Nicholas P
  • 1 Department of Anesthesia, ‡Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine , Stanford, California 94305, United States. , (United States)
Type
Published Article
Journal
ACS Chemical Neuroscience
Publisher
American Chemical Society
Publication Date
Dec 17, 2014
Volume
5
Issue
12
Pages
1246–1252
Identifiers
DOI: 10.1021/cn500172e
PMID: 25340635
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Anesthetics are thought to mediate a portion of their activity via binding to and modulation of potassium channels. In particular, tandem pore potassium channels (K2P) are transmembrane ion channels whose current is modulated by the presence of general anesthetics and whose genetic absence has been shown to confer a level of anesthetic resistance. While the exact molecular structure of all K2P forms remains unknown, significant progress has been made toward understanding their structure and interactions with anesthetics via the methods of molecular modeling, coupled with the recently released higher resolution structures of homologous potassium channels to act as templates. Such models reveal the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three- dimensional cavity that forms a putative anesthetic binding site. The model successfully predicts additional important residues that are also involved in the putative binding site as validated by the results of suggested experimental mutations. Such a model can now be used to further predict other amino acid residues that may be intimately involved in the target-based structure-activity relationships that are necessary for anesthetic binding.

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