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Two-pore domain potassium (K(2P)) channels play a key role in setting the membrane potential of excitable cells. Despite their role as putative targets for drugs and general anesthetics, little is known about the structure and the drug binding site of K(2P) channels. We describe A1899 as a potent and highly selective blocker of the K(2P) channel TASK-1. As A1899 acts as an open-channel blocker and binds to residues forming the wall of the central cavity, the drug was used to further our understanding of the channel pore. Using alanine mutagenesis screens, we have identified residues in both pore loops, the M2 and M4 segments, and the halothane response element to form the drug binding site of TASK-1. Our experimental data were used to validate a K(2P) open-pore homology model of TASK-1, providing structural insights for future rational design of drugs targeting K(2P) channels.

Original publication

DOI

10.1074/jbc.M111.227884

Type

Journal article

Journal

J Biol Chem

Publication Date

22/04/2011

Volume

286

Pages

13977 - 13984

Keywords

Alanine, Animals, Benzamides, Benzeneacetamides, Binding Sites, DNA, Complementary, Drug Design, Humans, Inhibitory Concentration 50, Models, Molecular, Mutagenesis, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Oocytes, Patch-Clamp Techniques, Potassium, Potassium Channel Blockers, Potassium Channels, Tandem Pore Domain, Protein Conformation, Xenopus laevis