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.
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Authors | Richard J Clark, Harald Fischer, Simon T Nevin, David J Adams, David J Craik |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 281
Issue 32
Pg. 23254-63
(Aug 11 2006)
ISSN: 0021-9258 [Print] United States |
PMID | 16754662
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Conotoxins
- Disulfides
- Peptides
- alpha-conotoxin Vc1.1
- Nicotine
- Proline
- Oxygen
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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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