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| Item Type: | Article |
|---|---|
| Title: | A pharmacological master key mechanism that unlocks the selectivity filter gate in K(+) channels |
| Creators Name: | Schewe, M., Sun, H., Mert, Ü., Mackenzie, A., Pike, A.C.W., Schulz, F., Constantin, C., Vowinkel, K.S., Conrad, L.J., Kiper, A.K., Gonzalez, W., Musinszki, M., Tegtmeier, M., Pryde, D.C., Belabed, H., Nazare, M., de Groot, B.L., Decher, N., Fakler, B., Carpenter, E.P., 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 |
| Volume: | 363 |
| Number: | 6429 |
| Page Range: | 875-880 |
| Date: | 22 February 2019 |
| Official Publication: | https://doi.org/10.1126/science.aav0569 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
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