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Papers In Press, published online ahead of print June 5, 2006
J. Biol. Chem, 10.1074/jbc.M604550200
Submitted on May 12, 2006
Accepted on June 5, 2006

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

Richard J. Clark, Harald Fischer, Simon T. Nevin, David J. Adams, and David J. Craik

Chemistry and Structural Biology, Institute for Molecular Bioscience, Brisbane, QLD 4072

Corresponding Author: d.craik{at}imb.uq.edu.au

The a-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 dependant manner and preferentially targets peripheral nAChR subtypes over central subtypes. Specifically, Vc1.1 is selective for a3-containing nAChR subtypes. The three dimensional structure of Vc1.1 comprises a small a-helix spanning residues P6 to D11 and is braced by the I-II, III-IV disulfide connectivity seen in other a-conotoxins. A comparison of the structure of Vc1.1 with other a-conotoxins, taken together with nAChR selectivity data, suggests that the conserved proline at position 6 is important for binding while a number of residues in the C-terminal portion of the peptide contribute towards 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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