An allosteric ligand-binding site in the extracellular cap of K2P channels

Qichao Luo, Liping Chen, Xi Cheng, Yuqin Ma, Xiaona Li, Bing Zhang, Li Li, Shilei Zhang, Fei Guo, Yang Li () and Huaiyu Yang ()
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Qichao Luo: Chinese Academy of Sciences
Liping Chen: Chinese Academy of Sciences
Xi Cheng: Chinese Academy of Sciences
Yuqin Ma: Chinese Academy of Sciences
Xiaona Li: Chinese Academy of Sciences
Bing Zhang: Chinese Academy of Sciences
Li Li: Chinese Academy of Sciences
Shilei Zhang: Soochow University
Fei Guo: Chinese Academy of Sciences
Yang Li: Chinese Academy of Sciences
Huaiyu Yang: Chinese Academy of Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are thus potential drug targets for treating diseases. Here, we identify N-(4-cholorphenyl)-N-(2-(3,4-dihydrosioquinolin-2(1H)-yl)-2-oxoethyl)methanesulfonamide (TKDC) as an inhibitor of the TREK subfamily, including TREK-1, TREK-2 and TRAAK channels. Using TKDC as a chemical probe, a study combining computations, mutagenesis and electrophysiology reveals a K2P allosteric ligand-binding site located in the extracellular cap of the channels. Molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway. Using virtual screening approach, we identify other inhibitors targeting the extracellular allosteric ligand-binding site of these channels. Overall, our results suggest that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins.

Date: 2017
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DOI: 10.1038/s41467-017-00499-3

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