Abstract
BackgroundCorreolide, 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.ResultsWe 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.ConclusionOur 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.
Highlights
Correolide, a nortriterpene isolated from the Costa Rican tree Spachea correa, is a novel immunosuppressant, which blocks Kv1.3 channels in human T lymphocytes
The length of correolide is ~16 Å, which is defined as the distance between the most remote points at the van der Waals surfaces of the opposite poles
The nucleophilic potential of the ligand is not matched by the inner vestibule of the channel, which is predominantly lined with hydrophobic residues in the inner helices
Summary
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. Potassium channels play fundamental roles in physiology by controlling the electrical activity of excitable cells [1]. Each domain contains a transmembrane outer helix, a membrane-diving P-loop, and a transmembrane inner helix. The P-loop comprises a pore helix, a selectivity-filter region with the potassium channel signature sequence TVGYG, and an extracellular linker to the inner helix. Voltage-gated K+ channels (Kv) contain large voltage-sensing domains linked to the N-termini of the outer helices. In the X-ray structures of bacterial K+ channels, KcsA [2] and KirBac [3], the cytoplasmic ends of the pore-lining inner helices converge to form a closed activation gate. KcsA co-crystallized with (page number not for citation purposes)
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