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

Science American Association for the Advancement of Science 363:6429 (2019) 875-880

Authors:

M Schewe, H Sun, Ü Mert, A Mackenzie, ACW Pike, F Schulz, C Constantin, KS Vowinkel, LJ Conrad, AK Kiper, W Gonzalez, M Musinszki, M Tegtmeier, DC Pryde, H Belabed, M Nazare, BL De Groot, N Decher, B Fakler, EP Carpenter, Stephen Tucker, T Baukrowitz

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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A Pharmacological Masterkey Mechanism to Unlock the Selectivity Filter Gate in K+ Channels

Biophysical Journal Elsevier 116:3 (2019) 301a-302a

Authors:

Marcus Schewe, Han Sun, Alexandra Mackenzie, Ashley CW Pike, Friederike Schulz, Christina Constantin, Aytug K Kiper, Linus J Conrad, Wendy Gonzalez, Bert L de Groot, Niels Decher, Bernd Fakler, Elisabeth P Carpenter, Stephen J Tucker, Thomas Baukrowitz
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Functional Annotation of Ion Channel Structures: Predicting Pore Solvation States Based on Local Radius and Hydrophobicity

Biophysical Journal Elsevier 116:3 (2019) 241a

Authors:

Shanlin Rao, Gianni Klesse, Phillip J Stansfeld, Stephen J Tucker, Mark SP Sansom
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Insights into Selectivity Filter Gating of K2P Channels from Single-Channel Recordings

Biophysical Journal Elsevier 116:3 (2019) 248a-249a

Authors:

Linus J Conrad, Stephen J Tucker
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Systematic Scanning Mutagenesis of the Pore Helices in the TREK-2 K2P Channel

Biophysical Journal Elsevier 116:3 (2019) 398a-399a

Authors:

Manuel Arcangeletti, Stephen J Tucker
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