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, David J. Craik

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Abstract

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 tetrodoxin-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 β-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 δ- and ω-conotoxins, which along with the μO-conotoxins are members of the O superfamily. Loop 2 of ω-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.

Original languageEnglish
Pages (from-to)25774-25782
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number24
DOIs
Publication statusPublished - 11 Jun 2004
Externally publishedYes

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Conotoxins
Sodium Channels
Tetrodotoxin
Sensory Receptor Cells
Neurons
Calcium Channels
Cystine
Spinal Ganglia
Electric potential
Disulfides
Nuclear magnetic resonance spectroscopy
Cysteine
Rats
Magnetic Resonance Spectroscopy
Sodium
Pain
Peptides
Molecules
Water
Pharmaceutical Preparations

Cite this

Daly, Norelle L. ; Ekberg, Jenny A. ; Thomas, Linda ; Adams, David J. ; Lewis, Richard J. ; Craik, David J. / Structures of μO-conotoxins from Conus marmoreus : Inhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian sensory neurons. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 24. pp. 25774-25782.
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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. / Daly, Norelle L.; Ekberg, Jenny A.; Thomas, Linda; Adams, David J.; Lewis, Richard J.; Craik, David J.

In: Journal of Biological Chemistry, Vol. 279, No. 24, 11.06.2004, p. 25774-25782.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Structures of μO-conotoxins from Conus marmoreus

T2 - Inhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian sensory neurons

AU - Daly, Norelle L.

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AU - Lewis, Richard J.

AU - Craik, David J.

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