Dan Roden
Faculty Member
Last active: 3/24/2020

KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting.

Wrobel E, Rothenberg I, Krisp C, Hundt F, Fraenzel B, Eckey K, Linders JT, Gallacher DJ, Towart R, Pott L, Pusch M, Yang T, Roden DM, Kurata HT, Schulze-Bahr E, Strutz-Seebohm N, Wolters D, Seebohm G
Nat Commun. 2016 7: 12795

PMID: 27731317 · PMCID: PMC5064022 · DOI:10.1038/ncomms12795

Most small-molecule inhibitors of voltage-gated ion channels display poor subtype specificity because they bind to highly conserved residues located in the channel's central cavity. Using a combined approach of scanning mutagenesis, electrophysiology, chemical ligand modification, chemical cross-linking, MS/MS-analyses and molecular modelling, we provide evidence for the binding site for adamantane derivatives and their putative access pathway in Kv7.1/KCNE1 channels. The adamantane compounds, exemplified by JNJ303, are highly potent gating modifiers that bind to fenestrations that become available when KCNE1 accessory subunits are bound to Kv7.1 channels. This mode of regulation by auxiliary subunits may facilitate the future development of potent and highly subtype-specific Kv channel inhibitors.

MeSH Terms (16)

Adamantane Allosteric Regulation Animals Binding Sites Cross-Linking Reagents Humans Ion Channel Gating KCNQ1 Potassium Channel Models, Molecular Mutagenesis Mutation Oocytes Potassium Channel Blockers Potassium Channels, Voltage-Gated Tandem Mass Spectrometry Xenopus laevis

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