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

Journal article

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.

Authors: Schewe, M; Sun, H; Mert, Ü; Mackenzie, A; Pike, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for the Advancement of Science
• Journal: Science
• Volume: 363
• Issue: 6429
• Pages: 875-880
• Publication date: 2019-02-22
• Acceptance date: 2019-01-28
• DOI: 10.1126/science.aav0569
• EISSN: 1095-9203
• ISSN: 0036-8075
• Language: English