Publication: Monte Carlo-energy minimization of correolide in the Kv1.3 channel: Possible role of potassium ion in ligand-receptor interactions
All || By Area || By Year| Title | Monte Carlo-energy minimization of correolide in the Kv1.3 channel: Possible role of potassium ion in ligand-receptor interactions | Authors/Editors* | I Bruhova, BS Zhorov |
|---|---|
| Where published* | BMC Struct. Biol. |
| How published* | Journal |
| Year* | 2007 |
| Volume | 7 |
| Number | 5 |
| Pages | 1-15 |
| Publisher | |
| Keywords | |
| Link | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17261195&query_hl=1&itool=pubmed_docsum |
| 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 |
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