Publication Date:
2019
Description:
〈p〉Potassium (K〈sup〉+〈/sup〉) 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〈sup〉+〈/sup〉 channels gated at their selectivity filter (SF), including many two-pore domain K〈sup〉+〈/sup〉 (K〈sub〉2P〈/sub〉) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca〈sup〉2+〈/sup〉)–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〈sup〉+〈/sup〉 occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K〈sup〉+〈/sup〉 channel activators and highlight a filter gating machinery that is conserved across different families of K〈sup〉+〈/sup〉 channels with implications for rational drug design.〈/p〉
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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