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


  • M. Schewe
  • H. Sun
  • Ü. Mert
  • A. Mackenzie
  • A.C.W. Pike
  • F. Schulz
  • C. Constantin
  • K.S. Vowinkel
  • L.J. Conrad
  • A.K. Kiper
  • W. Gonzalez
  • M. Musinszki
  • M. Tegtmeier
  • D.C. Pryde
  • H. Belabed
  • M. Nazare
  • B.L. de Groot
  • N. Decher
  • B. Fakler
  • E.P. Carpenter
  • S.J. Tucker
  • T. Baukrowitz


  • Science


  • Science 363 (6429): 875-880


  • 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(2P)) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca(2+))-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.