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Science. 2019 Feb 22;363(6429):875-880. doi: 10.1126/science.aav0569.

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

Author information

1
Institute of Physiology, Christian-Albrechts University of Kiel, 24118 Kiel, Germany. m.schewe@physiologie.uni-kiel.de t.baukrowitz@physiologie.uni-kiel.de.
2
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department of Structural Biology, 13125 Berlin, Germany.
3
Institute of Physiology, Christian-Albrechts University of Kiel, 24118 Kiel, Germany.
4
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
5
OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK.
6
Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
7
Institute of Physiology II, Albert-Ludwigs University of Freiburg, 79104 Freiburg, Germany.
8
Centers for Biological Signaling Studies CIBSS and BIOSS, 79104 Freiburg, Germany.
9
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 35037 Marburg, Germany.
10
Centro de Bioinformatica y Simulacion Molecular, Universidad de Talca, 3465548 Talca, Chile.
11
Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, 3465548 Talca, Chile.
12
Pfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridgeshire CB21 6GS, UK.
13
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department of Medicinal Chemistry, 13125 Berlin, Germany.
14
Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.

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.

PMID:
30792303
DOI:
10.1126/science.aav0569

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