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

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-0F71-E Version Permalink: http://hdl.handle.net/21.11116/0000-0003-1973-0
Genre: Journal Article

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 Creators:
Schewe, M., Author
Sun, H., Author
Mert, Ü., Author
Mackenzie, A., Author
Pike, A. C. W., Author
Schulz, F., Author
Constantin, C., Author
Vowinkel, K. S., Author
Conrad, L. J., Author
Kiper, A. K., Author
Gonzalez, W., Author
Musinszki, M., Author
Tegtmeier, M., Author
Pryde, D. C., Author
Belabed, H., Author
Nazare, M., Author
de Groot, B. L.1, Author              
Decher, N., Author
Fakler, B., Author
Carpenter, E. P., Author
Tucker, S. J., AuthorBaukrowitz, T., Author more..
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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 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.

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Language(s): eng - English
 Dates: 2019-02-22
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1126/science.aav0569
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Title: Science
Source Genre: Journal
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Pages: - Volume / Issue: 363 (6429) Sequence Number: - Start / End Page: 875 - 880 Identifier: -