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You are here: Home News A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels
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A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels

Schewe M, Constantin C et al, Science 363, 875–880 (2019)

Feb 22, 2019

 

Potassium 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 (K2P) channels, voltage-gated hERG (human-ether-a-go-go related gene) channels and calcium (Ca2+)-activated 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 poly-pharmacology 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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