Abstract
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.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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Chlorobenzenes / chemistry
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Chlorobenzenes / pharmacology*
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Cricetulus
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Crystallography, X-Ray
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Drug Design
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ERG1 Potassium Channel / agonists*
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ERG1 Potassium Channel / chemistry*
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HEK293 Cells
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Humans
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Ion Channel Gating / drug effects*
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Large-Conductance Calcium-Activated Potassium Channels / agonists*
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Large-Conductance Calcium-Activated Potassium Channels / chemistry*
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Molecular Dynamics Simulation
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Protein Domains
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Tetrahydronaphthalenes / chemistry
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Tetrahydronaphthalenes / pharmacology*
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Tetrazoles / chemistry
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Tetrazoles / pharmacology*
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Thiourea / analogs & derivatives*
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Thiourea / chemistry
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Thiourea / pharmacology
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Xenopus
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / pharmacology*
Substances
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(5,6,7,8-tetrahydronaphthalen-1-yl)-(2-(1H-tetrazol-5-yl)phenyl)amine
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1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-2-(1H-tetrazol-5-yl)phenyl)thiourea
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2-(4-(2-(3,4-dichlorophenyl)ethyl)phenylamino)benzoic acid
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Chlorobenzenes
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ERG1 Potassium Channel
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KCNH2 protein, human
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Large-Conductance Calcium-Activated Potassium Channels
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Tetrahydronaphthalenes
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Tetrazoles
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ortho-Aminobenzoates
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Thiourea