The synthesis, structural characterization, and receptor specificity of the α-conotoxin Vc1.1
RIS ID
105731
Abstract
The α-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 α3-containing nAChR subtypes. The three-dimensional structure of Vc1.1 comprises a small α-helix spanning residues Pro6 to Asp11 and is braced by the I-III, II-IV disulfide connectivity seen in other α-conotoxins. A comparison of the structure of Vc1.1 with other α-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.
Publication Details
Clark, R. J., Fischer, H., Nevin, S. T., Adams, D. J. & Craik, D. J. (2006). The synthesis, structural characterization, and receptor specificity of the α-conotoxin Vc1.1. Journal of Biological Chemistry, 281 (32), 23254-23263.