Abstract
Conotoxins are disulfide-rich peptides found in the venom of cone snails. Due to their exquisite potency and high selectivity for a wide range of voltage and ligand gated ion channels they are attractive drug leads in neuropharmacology. Recently, cone snails were found to have the capability to rapidly switch between venom types with different proteome profiles in response to predatory or defensive stimuli. A novel conotoxin, GXIA (original name G117), belonging to the I3-subfamily was identified as the major component of the predatory venom of piscivorous Conus geographus. Using 2D solution NMR spectroscopy techniques, we resolved the 3D structure for GXIA, the first structure reported for the I3-subfamily and framework XI family. The 32 amino acid peptide is comprised of eight cysteine residues with the resultant disulfide connectivity forming an ICK+1 motif. With a triple stranded β-sheet, the GXIA backbone shows striking similarity to several tarantula toxins targeting the voltage sensor of voltage gated potassium and sodium channels. Supported by an amphipathic surface, the structural evidence suggests that GXIA is able to embed in the membrane and bind to the voltage sensor domain of a putative ion channel target.
Highlights
In addition to 1 H homonuclear data 2D 1 H-13 C and 1 H-15 N heteronuclear singlequantum correlation spectroscopy (HSQC), data were recorded at natural abundance, utilising the excellent sensitivity and signal-to-noise of the cryoprobe
GXIA belongs to the I3 superfamily, for which no pharmacological activity has been reported to date; it was of interest to characterize structures or pharmacological activity has been reported to date; it was of interest this peptide further
GXIA is the first reported structure for a conotoxin belonging to the I3 subfamily, and only the second structure after ι-RXIA from the I-superfamily, which currently contains
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The peptide toxins can be highly selective for individual sub-type members of ion channel families, a key feature that makes them desirable drug candidates with limited side effects due to off target activity [7]. Structure determination is an important step in developing structure activity relationships to understand conotoxin function on a molecular level Due to their desirable pharmacological properties and natural diversity, conotoxins have been identified as potential drug leads for a range of neurological conditions. A prominent component of the C. geographus’ predatory venom was the novel GXIA conotoxin, a 32 amino acid peptide with eight Cys residues The spacing of these Cys residues (C–C–CC–CC–C–C) gives it an ‘XI’ framework, while GXIA is a member of the I superfamily and part of the I3 subfamily, based on its signal peptide sequence [17]. NMR spectroscopy to elucidate its 3D structure and identify key structural characteristics to gain new insights into its biological activity
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