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Journal Article

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

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de Groot,  B. L.
Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society;

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3029803.pdf
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Supplementary Material (public)

3029803_Suppl.DC1
(Supplementary material), 55KB

Citation

Schewe, M., Sun, H., Mert, Ü., Mackenzie, A., Pike, A. C. W., Schulz, F., et al. (2019). A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels. Science, 363(6429), 875-880. doi:10.1126/science.aav0569.


Cite as: http://hdl.handle.net/21.11116/0000-0003-0F71-E
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.