title: Monte Carlo-energy minimization of correolide in the Kv1.3 channel: possible role of potassium ion in ligand-receptor interactions.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, L8N 3Z5, Canada. bruhovi@mcmaster.ca <bruhovi@mcmaster.ca>
authors.forename: Iva
authors.initials: I
authors.lastname: Bruhova
authors.forename: Boris S
authors.initials: BS
authors.lastname: Zhorov
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008024:Ligands; D009010:Monte Carlo Method; D014315:Triterpenes / Q000493:pharmacokinetics*
chemical_list: D051664:Kv1.3 Potassium Channel; D008024:Ligands; D014315:Triterpenes; C118657:correolide