Side pockets provide the basis for a new mechanism of Kv channel-specific inhibition

Nat Chem Biol. 2013 Aug;9(8):507-13. doi: 10.1038/nchembio.1271. Epub 2013 Jun 2.


Most known small-molecule inhibitors of voltage-gated ion channels have poor subtype specificity because they interact with a highly conserved binding site in the central cavity. Using alanine-scanning mutagenesis, electrophysiological recordings and molecular modeling, we have identified a new drug-binding site in Kv1.x channels. We report that Psora-4 can discriminate between related Kv channel subtypes because, in addition to binding the central pore cavity, it binds a second, less conserved site located in side pockets formed by the backsides of S5 and S6, the S4-S5 linker, part of the voltage sensor and the pore helix. Simultaneous drug occupation of both binding sites results in an extremely stable nonconducting state that confers high affinity, cooperativity, use-dependence and selectivity to Psora-4 inhibition of Kv1.x channels. This new mechanism of inhibition represents a molecular basis for the development of a new class of allosteric and selective voltage-gated channel inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ficusin / chemistry
  • Ficusin / pharmacology
  • Kv1.5 Potassium Channel / antagonists & inhibitors*
  • Kv1.5 Potassium Channel / chemistry*
  • Kv1.5 Potassium Channel / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Substrate Specificity


  • 5-(4-phenylbutoxy)psoralen
  • Kv1.5 Potassium Channel
  • Ficusin