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Science
2019 Feb 22;3636429:875-880. doi: 10.1126/science.aav0569.
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A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels.
Schewe M
,
Sun H
,
Mert Ü
,
Mackenzie A
,
Pike ACW
,
Schulz F
,
Constantin C
,
Vowinkel KS
,
Conrad LJ
,
Kiper AK
,
Gonzalez W
,
Musinszki M
,
Tegtmeier M
,
Pryde DC
,
Belabed H
,
Nazare M
,
de Groot BL
,
Decher N
,
Fakler B
,
Carpenter EP
,
Tucker SJ
,
Baukrowitz T
.
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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.
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