Download MendeleyThe Synthesis, Structural Characterization, and Receptor Specificity of the {alpha}-Conotoxin Vc1.1.
Clark, R.J., Fischer, H., Nevin, S.T., Adams, D.J., Craik, D.J.(2006) J Biol Chem 281: 23254-23263
- PubMed: 16754662
- DOI: https://doi.org/10.1074/jbc.M604550200
- Primary Citation of Related Structures:
2H8S - PubMed Abstract:
The alpha-conotoxin Vc1.1 is a small disulfide-bonded peptide currently in development as a treatment for neuropathic pain. This study describes the synthesis, determination of the disulfide connectivity, and the determination of the three-dimensional structure of Vc1.1 using NMR spectroscopy. Vc1.1 was shown to inhibit nicotine-evoked membrane currents in isolated bovine chromaffin cells in a concentration-dependent manner and preferentially targets peripheral nicotinic acetylcholine receptor (nAChR) subtypes over central subtypes. Specifically, Vc1.1 is selective for alpha3-containing nAChR subtypes. The three-dimensional structure of Vc1.1 comprises a small alpha-helix spanning residues Pro6 to Asp11 and is braced by the I-III, II-IV disulfide connectivity seen in other alpha-conotoxins. A comparison of the structure of Vc1.1 with other alpha-conotoxins, taken together with nAChR selectivity data, suggests that the conserved proline at position 6 is important for binding, whereas a number of residues in the C-terminal portion of the peptide contribute toward the selectivity. The structure reported here should open new opportunities for further development of Vc1.1 or analogues as analgesic agents.
Organizational Affiliation:
Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia.
