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Nat Commun. 2016 Oct 12;7:12795. doi: 10.1038/ncomms12795.

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

Author information

1
Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.
2
Department of Analytical Chemistry, Ruhr University of Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.
3
Project Management Office, Janssen Research &Development, a Division of Janssen Pharmaceutica N.V., 2340 Beerse, Belgium.
4
Safety Pharmacology Research, Translational Sciences, Janssen Research &Development, a Division of Janssen Pharmaceutica N.V., 2340 Beerse, Belgium.
5
Institute of Physiology, Ruhr University of Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.
6
Istituto di Biofisica CNR, Via De Marini 6, Genova I-16149, Italy.
7
Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
8
Departments of Medicine, Pharmacology and Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
9
Department of Pharmacology, University of Alberta, 9-70 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2R3.
10
Interdisciplinary Centre for Clinical Research (IZKF), Faculty of Medicine, University of Münster, Münster D-48149, Germany.

Abstract

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.

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