Abstract
Conopeptides belonging to the A-superfamily from the venomous molluscs, Conus, 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 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 α-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.
Highlights
Cone snail venoms comprise mainly small peptides, termed conotoxins, and represent one of the most extensive libraries of bioactive compounds from marine creatures
Several conotoxins have been tested in clinical trials, with an N-type calcium channel blocker from Conus magus (ω-MVIIA) approved by the Federal Drug Administration (FDA) as Prialt® for the treatment of chronic pain [2,3,4]
A major isomer was present in the oxidation reaction and was purified using reversed-phase high performance liquid chromatography (RP-HPLC) and the mass analysed using matrix-assisted laser desorption ionisation (MALDI)-TOF mass spectrometry
Summary
Cone snail venoms comprise mainly small peptides, termed conotoxins, and represent one of the most extensive libraries of bioactive compounds from marine creatures. 20 residues length, have a CysI-CysIII, CysII-CysIV conservation, in addition to classification families in based on cysteine framework and receptor disulfide connectivity and the majority have a 4/7 loop which represents. The A-superfamily is one of the nAChRs. 4/7 the α-conotoxins target different heteromeric homomeric neuronal most welland characterised, majority containing cysteine frameworkand/or. 4/7 the α-conotoxins target different heteromeric homomeric neuronal most welland characterised, majority containing cysteine frameworkand/or NAChRs exist as homopentamers or heteropentamers comprising a range of different family, the majority of α-conotoxins are characterised by a small helical structure, which is braced subunits [17]. Despite the variation in inter-cysteine loop sizes across the family, the majority of α-conotoxins are characterised by a small helical structure, which is braced by the. Channels, indicating that it might represent a new pharmacological class of A-superfamily toxin
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