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J. Biol. Chem., Vol. 281, Issue 32, 23254-23263, August 11, 2006

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The Synthesis, Structural Characterization, and Receptor Specificity of the -Conotoxin Vc1.1^*

Richard J. Clark¹, Harald Fischer¹, Simon T. Nevin¹, David J. Adams, and David J. Craik²

From the Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia

The -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 3-containing nAChR subtypes. The three-dimensional structure of Vc1.1 comprises a small -helix spanning residues Pro⁶ to Asp¹¹ and is braced by the I-III, II-IV disulfide connectivity seen in other -conotoxins. A comparison of the structure of Vc1.1 with other -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.

Received for publication, May 12, 2006

The atomic coordinates and structure factors (code 2H8S) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by funding from the Australian Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² An Australian Research Council Professorial Fellow. To whom correspondence should be addressed. Tel.: 61-7-3346-2019; Fax: 61-7-3346-2029; E-mail: d.craik{at}imb.uq.edu.au.

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