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

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.