Monte Carlo-energy minimization of correolide in the Kv1.3 channel: possible role of potassium ion in ligand-receptor interactions

BMC Struct Biol. 2007 Jan 29;7:5. doi: 10.1186/1472-6807-7-5.

Abstract

Background: Correolide, a nortriterpene isolated from the Costa Rican tree Spachea correa, is a novel immunosuppressant, which blocks Kv1.3 channels in human T lymphocytes. Earlier mutational studies suggest that correolide binds in the channel pore. Correolide has several nucleophilic groups, but the pore-lining helices in Kv1.3 are predominantly hydrophobic raising questions about the nature of correolide-channel interactions.

Results: We employed the method of Monte Carlo (MC) with energy minimization to search for optimal complexes of correolide in Kv1.2-based models of the open Kv1.3 with potassium binding sites 2/4 or 1/3/5 loaded with K+ ions. The energy was MC-minimized from many randomly generated starting positions and orientations of the ligand. In all the predicted low-energy complexes, oxygen atoms of correolide chelate a K+ ion. Correolide-sensing residues known from mutational analysis along with the ligand-bound K+ ion provide major contributions to the ligand-binding energy. Deficiency of K+ ions in the selectivity filter of C-type inactivated Kv1.3 would stabilize K+-bound correolide in the inner pore.

Conclusion: Our study explains the paradox that cationic and nucleophilic ligands bind to the same region in the inner pore of K+ channels and suggests that a K+ ion is an important determinant of the correolide receptor and possibly receptors of other nucleophilic blockers of the inner pore of K+ channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computational Biology
  • Drug Design
  • Humans
  • Ion Channel Gating
  • Kv1.3 Potassium Channel / antagonists & inhibitors
  • Kv1.3 Potassium Channel / metabolism*
  • Ligands
  • Monte Carlo Method
  • Triterpenes / pharmacokinetics*

Substances

  • Kv1.3 Potassium Channel
  • Ligands
  • Triterpenes
  • correolide