The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel

Fletcher, Jamie I, Chapman, Bogdan E., Mackay, Joel P., Howden, Merlin E. H. and King, Glenn F. (1997) The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel. Structure, 5 11: 1525-1535. doi:10.1016/S0969-2126(97)00301-8

Author Fletcher, Jamie I
Chapman, Bogdan E.
Mackay, Joel P.
Howden, Merlin E. H.
King, Glenn F.
Title The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel
Journal name Structure   Check publisher's open access policy
ISSN 0969-2126
Publication date 1997-11-01
Year available 1997
Sub-type Article (original research)
DOI 10.1016/S0969-2126(97)00301-8
Open Access Status DOI
Volume 5
Issue 11
Start page 1525
End page 1535
Total pages 11
Place of publication Cambridge, Mass.
Publisher Cell Press
Language eng
Subject 111506 Toxicology (incl.Clinical Toxicology)
060112 Structural Biology (incl. Macromolecular Modelling)
Abstract Background: Versutoxin (delta-ACTX-Hv1) is the major component of the venom of the Australian Blue Mountains funnel web spider, Hadronyche versuta. delta-ACTX-Hv1 produces potentially fatal neurotoxic symptoms in primates by slowing the inactivation of voltage-gated sodium channels; delta-ACTX-Hv1 is therefore a useful tool for studying sodium channel function. We have determined the three-dimensional structure of delta ACTX-Hv1 as the first step towards understanding the molecular basis of its interaction with these channels. Results: The solution structure of delta-ACTX-Hv1, determined using NMR spectroscopy, comprises a core beta region containing a triple-stranded antiparallel beta sheet, a thumb-like extension protruding from the beta region and a C-terminal 3(10) helix that is appended to the beta domain by virtue of a disulphide bond. The beta region contains a cystine knot motif similar to that seen in other neurotoxic polypeptides. The structure shows homology with mu-agatoxin-l, a spider toxin that also modifies the inactivation kinetics of vertebrate voltage-gated sodium channels. More surprisingly, delta-ACTX-Hv1 shows both sequence and structural homology with gurmarin, a plant polypeptide. This similarity leads us to suggest that the sweet-taste suppression elicited by gurmarin may result from an interaction with one of the downstream ion channels involved in sweet-taste transduction. Conclusions: delta-ACTX-Hv1 shows no structural homology with either sea anemone or alpha-scorpion toxins, both of which also modify the inactivation kinetics of voltage-gated sodium channels by interacting with channel recognition site 3. However, we have shown that delta-ACTX-Hv1 contains charged residues that are topologically related to those implicated in the binding of sea anemone and alpha-scorpion toxins to mammalian voltage-gated sodium channels, suggesting similarities in their mode of interaction with these channels.
Keyword Biochemistry & Molecular Biology
Cell Biology
Alpha-scorpion Toxin
Sodium Channel Inactivation
Funnel-web Spider
Polypeptide Anthopleurin-b
Androctonus-australis Hector
Amino-acid Sequence
3-dimensional Structure
Distance Geometry
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 98 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 14 Aug 2007, 03:03:15 EST