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J. Biol. Chem., Vol. 279, Issue 24, 25774-25782, June 11, 2004

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Structures of µO-conotoxins from Conus marmoreus

INHIBITORS OF TETRODOTOXIN (TTX)-SENSITIVE AND TTX-RESISTANT SODIUM CHANNELS IN MAMMALIAN SENSORY NEURONS^*

Norelle L. Daly, Jenny A. Ekberg¶, Linda Thomas, David J. Adams¶, Richard J. Lewis¶||, and David J. Craik**

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

The µO-conotoxins are an intriguing class of conotoxins targeting various voltage-dependent sodium channels and molluscan calcium channels. In the current study, we have shown MrVIA and MrVIB to be the first known peptidic inhibitors of the transient tetrodotoxin-resistant (TTX-R) Na⁺ current in rat dorsal root ganglion neurons, in addition to inhibiting tetrodotoxin-sensitive Na⁺ currents. Human TTX-R sodium channels are a therapeutic target for indications such as pain, highlighting the importance of the µO-conotoxins as potential leads for drug development. Furthermore, we have used NMR spectroscopy to provide the first structural information on this class of conotoxins. MrVIA and MrVIB are hydrophobic peptides that aggregate in aqueous solution but were solubilized in 50% acetonitrile/water. The three-dimensional structure of MrVIB consists of a small -sheet and a cystine knot arrangement of the three-disulfide bonds. It contains four backbone "loops" between successive cysteine residues that are exposed to the solvent to varying degrees. The largest of these, loop 2, is the most disordered part of the molecule, most likely due to flexibility in solution. This disorder is the most striking difference between the structures of MrVIB and the known - and -conotoxins, which along with the µO-conotoxins are members of the O superfamily. Loop 2 of -conotoxins has previously been shown to contain residues critical for binding to voltage-gated calcium channels, and it is interesting to speculate that the flexibility observed in MrVIB may accommodate binding to both sodium and molluscan calcium channels.

Received for publication, December 1, 2003 , and in revised form, March 24, 2004.

The atomic coordinates and structure factors (code 1RMK) 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 a grant from the Australian Research Council (to D. J. C., R. J. L., and D. J. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Table S1.

Both authors contributed equally to this work.

^** An Australian Research Council Senior Fellow. To whom correspondence may be addressed. Tel.: 61-7-3346-2109; Fax: 61-7-3346-2029; E-mail: d.craik{at}imb.uq.edu.au.

^|| To whom correspondence may be addressed. Tel.: 61-7-3346-2109; Fax: 61-7-3346-2029; E-mail: rlewis{at}imb.uq.edu.au.

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