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Wilson, David T.; Bansal, Paramjit S.; Carter, David A.; Vetter, Irina; Nicke, Annette; Dutertre, Sebastien; Daly, Norelle L. (2020): Characterisation of a Novel A-Superfamily Conotoxin. In: Biomedicines, Vol. 8, No. 5, 128
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Abstract

Conopeptides belonging to the A-superfamily from the venomous molluscs, Conus, are typically alpha-conotoxins. The alpha-conotoxins are of interest as therapeutic leads and pharmacological tools due to their selectivity and potency at nicotinic acetylcholine receptor (nAChR) subtypes. Structurally, the alpha-conotoxins have a consensus fold containing two conserved disulfide bonds that define the two-loop framework and brace a helical region. Here we report on a novel alpha-conotoxin Pl168, identified from the transcriptome of Conus planorbis, which has an unusual 4/8 loop framework. Unexpectedly, NMR determination of its three-dimensional structure reveals a new structural type of A-superfamily conotoxins with a different disulfide-stabilized fold, despite containing the conserved cysteine framework and disulfide connectivity of classical alpha-conotoxins. The peptide did not demonstrate activity on a range of nAChRs, or Ca2+ and Na+ channels suggesting that it might represent a new pharmacological class of conotoxins.