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The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1.

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.
AuthorsRichard J Clark, Harald Fischer, Simon T Nevin, David J Adams, David J Craik
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 32 Pg. 23254-63 (Aug 11 2006) ISSN: 0021-9258 [Print] United States
PMID16754662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Conotoxins
  • Disulfides
  • Peptides
  • alpha-conotoxin Vc1.1
  • Nicotine
  • Proline
  • Oxygen
Topics
  • Adrenal Glands (cytology)
  • Amino Acid Sequence
  • Animals
  • Cattle
  • Chromaffin Cells (cytology, metabolism)
  • Conotoxins (chemistry, metabolism)
  • Disulfides (chemistry)
  • Electrophysiology
  • Kinetics
  • Magnetic Resonance Spectroscopy (methods)
  • Models, Molecular
  • Molecular Sequence Data
  • Nicotine (pharmacology)
  • Oocytes (metabolism)
  • Oxygen (metabolism)
  • Peptides (chemistry)
  • Proline (chemistry)
  • Protein Binding
  • Protein Folding
  • Xenopus

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