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Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca2+)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design.

Original publication




Journal article



Publication Date





875 - 880


Animals, CHO Cells, Chlorobenzenes, Cricetulus, Crystallography, X-Ray, Drug Design, ERG1 Potassium Channel, HEK293 Cells, Humans, Ion Channel Gating, Large-Conductance Calcium-Activated Potassium Channels, Molecular Dynamics Simulation, Protein Domains, Tetrahydronaphthalenes, Tetrazoles, Thiourea, Xenopus, ortho-Aminobenzoates