Characterisation of a Novel A-Superfamily Conotoxin

• Published in: Biomedicines 2020-05, Vol.8 (5), p.128
• Main Authors: Wilson, David T, Bansal, Paramjit S, Carter, David A, Vetter, Irina, Nicke, Annette, Dutertre, Sébastien, Daly, Norelle L
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (nicotinic); Biological activity; Calcium channels; Chemical bonds; Chemical Sciences; conopeptide; Conotoxins; Conus; Disulfide bonds; disulfide framework; Gene expression; NMR; NMR spectroscopy; Nuclear magnetic resonance; Organic chemistry; Pain; Peptides; Sodium channels; Solvents
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/BIOMEDICINES8050128

Conopeptides belonging to the A-superfamily from the venomous molluscs, , are typically α-conotoxins. The α-conotoxins are of interest as therapeutic leads and pharmacological tools due to their selectivity and potency at nicotinic acetylcholine receptor (nAChR) subtypes. Structurally, the α-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 α-conotoxin Pl168, identified from the transcriptome of , 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 α-conotoxins. The peptide did not demonstrate activity on a range of nAChRs, or Ca and Na channels suggesting that it might represent a new pharmacological class of conotoxins.