Affiliations: Department of Physics, Indian Institute of Science,
Bangalore 560 012, India | Bioinformatics Centre, Indian Institute of Science,
Bangalore 560 012, India
Abstract: A novel conotoxin pl14a containing 25 amino acid residues with an
amidated C-terminus from vermivorous cone snail, Conus planorbis belongs
to J-conotoxin superfamily and this is the first conotoxin, which inhibits both
nicotinic acetylcholine receptor subtypes and Kv1.6 channel. We have attempted
through bioinformatics approaches to elucidate the extent of specificity of
pl14a towards Kv1 channel subtypes (Kv1.1-Kv1.6). Our work provides rationale
for the relatively high specificity and binding mode of pl14a to Kv1.6
channel.The pl14a peptide contains two types of structural elements, namely the
putative dyad (Lys18 and Tyr19) and basic residue ring constituted of arginine
residues. We have carried out in silico docking studies so as to assess
the contribution of one or combination of both structural elements of pl14a in
blocking of Kv1.6 channel. For this purpose, we have built by homology
modelling, the theoretical 3D structure of Kv1.6 channel based on the available
crystal structure of mammalian shaker Kv1.2 channel. Docking studies suggest
that positively charged residues ring may be involved in the blocking mechanism
of Kv1.6 channel. The models suggest that the peptide interacts with negatively
charged extracellular loops and pore-mouth of the potassium channel and blocks
the channel by covering the pore as a lid, akin to previously proposed blocking
mechanism of κM-conotoxin RIIIK from Conus
radiatus to Tsha1 potassium channel. The newly detected pharmacophore for
pl14a interacting with Kv1.6 channel provides a pointer to experimental work to
validate the observations made here. Based on differences in the number and
distribution of the positively-charged residues in other conopeptides from the
J-superfamily, we hypothesize different selectivity profiles against subtypes
of the potassium channels for these conopeptides.
