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

Science. 2019 Feb 22;363(6429):875-880. doi: 10.1126/science.aav0569.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Chlorobenzenes / chemistry
  • Chlorobenzenes / pharmacology*
  • Cricetulus
  • Crystallography, X-Ray
  • Drug Design
  • ERG1 Potassium Channel / agonists*
  • ERG1 Potassium Channel / chemistry*
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / drug effects*
  • Large-Conductance Calcium-Activated Potassium Channels / agonists*
  • Large-Conductance Calcium-Activated Potassium Channels / chemistry*
  • Molecular Dynamics Simulation
  • Protein Domains
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / pharmacology*
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*
  • Thiourea / analogs & derivatives*
  • Thiourea / chemistry
  • Thiourea / pharmacology
  • Xenopus
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / pharmacology*

Substances

  • (5,6,7,8-tetrahydronaphthalen-1-yl)-(2-(1H-tetrazol-5-yl)phenyl)amine
  • 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-2-(1H-tetrazol-5-yl)phenyl)thiourea
  • 2-(4-(2-(3,4-dichlorophenyl)ethyl)phenylamino)benzoic acid
  • Chlorobenzenes
  • ERG1 Potassium Channel
  • KCNH2 protein, human
  • Large-Conductance Calcium-Activated Potassium Channels
  • Tetrahydronaphthalenes
  • Tetrazoles
  • ortho-Aminobenzoates
  • Thiourea