A pharmacological master key mechanism that unlocks the selectivity filter gate in K + channels

• DOI: 10.1126/science.aav0569
• Publication Date: 2019-02-22T00:06:22Z
• Authors: Marcus Schewe; Han Sun; Ümit Mert; Alexandra Mackenzie; Ashley C. W. Pike; Friederike Schulz; Cristina Constantin; Kirsty S. Vowinkel; Linus J. Conrad; Aytug K. Kiper; Wendy Gonzalez; Marianne Musinszki; Marie Tegtmeier; David C. Pryde; Hassane Belabed; Marc Nazare; Bert L. de Groot; Niels Decher; Bernd Fakler; Elisabeth P. Carp...; Stephen J. Tucker; Thomas Baukrowitz
• Keywords: ERG1 Potassium Channel; 0303 health sciences; Tetrahydronaphthalenes; Xenopus; Thiourea; 610; Tetrazoles; CHO Cells; Molecular Dynamics Simulation; Chlorobenzenes; Crystallography, X-Ray; 03 medical and health sciences; Cricetulus; HEK293 Cells; Protein Domains; Drug Design; Animals; Humans; ortho-Aminobenzoates; Large-Conductance Calcium-Activated Potassium Channels; Ion Channel Gating

A key to potassium channel activation Using drugs activate channels has the potential treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with defined pharmacore that use similar mechanism many types channels. X-ray crystallography, functional analysis, molecular dynamics simulations showed NCAs bind below selectivity filter open gate Targeting this NCA site might be exploited in rational drug design. Science , issue p. 875