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

Item Type:Article
Title:A pharmacological master key mechanism that unlocks the selectivity filter gate in K(+) channels
Creators Name:Schewe, M. and Sun, H. and Mert, Ü. and Mackenzie, A. and Pike, A.C.W. and Schulz, F. and Constantin, C. and Vowinkel, K.S. and Conrad, L.J. and Kiper, A.K. and Gonzalez, W. and Musinszki, M. and Tegtmeier, M. and Pryde, D.C. and Belabed, H. and Nazare, M. and de Groot, B.L. and Decher, N. and Fakler, B. and Carpenter, E.P. and Tucker, S.J. and Baukrowitz, T.
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(+)(K(2P)) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca(2+))-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.
Keywords:CHO Cells, Chlorobenzenes, Drug Design, ERG1 Potassium Channel, HEK293 Cells, Ion Channel Gating, Large-Conductance Calcium-Activated Potassium Channels, Molecular Dynamics Simulation, Protein Domains, Tetrahydronaphthalenes, Tetrazoles, Thiourea, ortho-Aminobenzoates, X-Ray Crystallography, Animals, Cricetulus, Xenopus
Source:Science
ISSN:0036-8075
Publisher:American Association for the Advancement of Science (U.S.A.)
Volume:363
Number:6429
Page Range:875-880
Date:22 February 2019
Official Publication:https://doi.org/10.1126/science.aav0569
PubMed:View item in PubMed

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