Publications associated with Ion Channels

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

Science (New York, N.Y.) 363 (2019) 875-880

M Schewe, H Sun, Ü Mert, A Mackenzie, ACW Pike, F Schulz, C Constantin, KS Vowinkel, LJ Conrad, AK Kiper, W Gonzalez, M Musinszki, M Tegtmeier, DC Pryde, H Belabed, M Nazare, BL de Groot, N Decher, B Fakler, EP Carpenter, SJ Tucker, T Baukrowitz

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.

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