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

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Science  22 Feb 2019:
Vol. 363, Issue 6429, pp. 875-880
DOI: 10.1126/science.aav0569

A key to potassium channel activation

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

Science, this issue p. 875


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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