The Synthesis, Structural Characterization, and Receptor Specificity of the Alpha-conotoxin Vc1.1.
From: Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia.
The Journal of biological chemistry
- Publish Date: Aug 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 32
- Pages: 23254-63
- Medium: Print
- Language: English
- Citation (JAMA): Clark Richard J, Fischer Harald, Nevin Simon T, et al. The Synthesis, Structural Characterization, and Receptor Specificity of the Alpha-conotoxin Vc1.1.. J. Biol. Chem. Aug 2006;281:23254-63
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.
Mesh Headings (Keywords): Adrenal Glands, Amino Acid Sequence, Animals, Cattle, Chromaffin Cells, Conotoxins, Disulfides, Electrophysiology, Kinetics, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Nicotine, Oocytes, Oxygen, Peptides, Proline, Protein Binding, Protein Folding, Xenopus
Check for Full Text / PubMed Unique Identifier (PMID): 16754662
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