A pharmacological master key mechanism that unlocks the selectivity filter gate in K+channels
Schewe M., Sun H., Mert Ü., Mackenzie A., Pike ACW., Schulz F., Constantin C., Vowinkel KS., Conrad LJ., Kiper AK., Gonzalez W., Musinszki M., Tegtmeier M., Pryde DC., Belabed H., Nazare M., de Groot BL., Decher N., Fakler B., Carpenter EP., Tucker SJ., Baukrowitz T.
<jats:p>Potassium (K<jats:sup>+</jats:sup>) 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<jats:sup>+</jats:sup>channels gated at their selectivity filter (SF), including many two-pore domain K<jats:sup>+</jats:sup>(K<jats:sub>2P</jats:sub>) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca<jats:sup>2+</jats:sup>)–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<jats:sup>+</jats:sup>occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K<jats:sup>+</jats:sup>channel activators and highlight a filter gating machinery that is conserved across different families of K<jats:sup>+</jats:sup>channels with implications for rational drug design.</jats:p>