Details

Autor(en) / Beteiligte

• Schewe, Marcus
• Sun, Han
• Mert, Ümit
• Mackenzie, Alexandra
• Pike, Ashley C W
• Schulz, Friederike
• Constantin, Cristina
• Vowinkel, Kirsty S
• Conrad, Linus J
• Kiper, Aytug K
• Gonzalez, Wendy
• Musinszki, Marianne
• Tegtmeier, Marie
• Pryde, David C
• Belabed, Hassane
• Nazare, Marc
• de Groot, Bert L
• Decher, Niels
• Fakler, Bernd
• Carpenter, Elisabeth P
• Tucker, Stephen J
• Baukrowitz, Thomas

Titel

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

Ist Teil von

• Science (American Association for the Advancement of Science), 2019-02, Vol.363 (6429), p.875-880

Ort / Verlag

United States: The American Association for the Advancement of Science

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Science Online_科学在线

Beschreibungen/Notizen

• 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 ) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca )-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.