| Structural highlights
Function
[TXDT1_HADVE] Inhibits tetrodotoxin-sensitive voltage-gated sodium channels (Nav) by binding to site 3. Slows the inactivation, and causes a prolongation of action potential duration resulting in repetitive firing in autonomic and motor nerve fibers. Does not depolarize the resting potential. Does not affect tetrodotoxin-resistant sodium channels. This lethal neurotoxin is active on both insect and mammalian voltage-gated sodium channels. Pan-neuronal expression in Drosophila is lethal but flies engineered to express the toxin only in pacemaker neurons have profound defects in circadian rhythm but a normal lifespan.[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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 310 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-I, 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.
The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel.,Fletcher JI, Chapman BE, Mackay JP, Howden ME, King GF Structure. 1997 Nov 15;5(11):1525-35. PMID:9384567[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chieng B, Howden ME, Christie MJ. Australian funnel-web spider toxin, versutoxin, enhances spontaneous synaptic activity in single brain neurons in vitro. Brain Res. 1993 Oct 29;626(1-2):136-42. PMID:8281423
- ↑ Nicholson GM, Willow M, Howden ME, Narahashi T. Modification of sodium channel gating and kinetics by versutoxin from the Australian funnel-web spider Hadronyche versuta. Pflugers Arch. 1994 Oct;428(3-4):400-9. PMID:7816562
- ↑ Nicholson GM, Little MJ, Tyler M, Narahashi T. Selective alteration of sodium channel gating by Australian funnel-web spider toxins. Toxicon. 1996 Nov-Dec;34(11-12):1443-53. PMID:9028001
- ↑ Little MJ, Wilson H, Zappia C, Cestele S, Tyler MI, Martin-Eauclaire MF, Gordon D, Nicholson GM. Delta-atracotoxins from Australian funnel-web spiders compete with scorpion alpha-toxin binding on both rat brain and insect sodium channels. FEBS Lett. 1998 Nov 20;439(3):246-52. PMID:9845331
- ↑ Grolleau F, Stankiewicz M, Birinyi-Strachan L, Wang XH, Nicholson GM, Pelhate M, Lapied B. Electrophysiological analysis of the neurotoxic action of a funnel-web spider toxin, delta-atracotoxin-HV1a, on insect voltage-gated Na+ channels. J Exp Biol. 2001 Feb;204(Pt 4):711-21. PMID:11171353
- ↑ Gilles N, Harrison G, Karbat I, Gurevitz M, Nicholson GM, Gordon D. Variations in receptor site-3 on rat brain and insect sodium channels highlighted by binding of a funnel-web spider delta-atracotoxin. Eur J Biochem. 2002 Mar;269(5):1500-10. PMID:11874465
- ↑ Wu Y, Cao G, Pavlicek B, Luo X, Nitabach MN. Phase coupling of a circadian neuropeptide with rest/activity rhythms detected using a membrane-tethered spider toxin. PLoS Biol. 2008 Nov 4;6(11):e273. doi: 10.1371/journal.pbio.0060273. PMID:18986214 doi:http://dx.doi.org/10.1371/journal.pbio.0060273
- ↑ Fletcher JI, Chapman BE, Mackay JP, Howden ME, King GF. The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel. Structure. 1997 Nov 15;5(11):1525-35. PMID:9384567
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