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ACS Chem Neurosci. 2014 Dec 17;5(12):1246-52. doi: 10.1021/cn500172e. Epub 2014 Oct 31.

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

Author information

1
Department of Anesthesia, ‡Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine , Stanford, California 94305, United States.

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.

KEYWORDS:

Tandem pore potassium channel; anesthesia; homology modeling

PMID:
25340635
PMCID:
PMC4306477
DOI:
10.1021/cn500172e
[Indexed for MEDLINE]
Free PMC Article

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