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| - | [[Image:1vtx.jpg|left|200px]]<br /><applet load="1vtx" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1vtx" /> | |
| - | '''DELTA-ATRACOTOXIN-HV1 (VERSUTOXIN) FROM HADRONYCHE VERSUTA, NMR, 20 STRUCTURES'''<br /> | |
| | | | |
| - | ==Overview== | + | ==DELTA-ATRACOTOXIN-HV1 (VERSUTOXIN) FROM HADRONYCHE VERSUTA, NMR, 20 STRUCTURES== |
| - | 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. | + | <StructureSection load='1vtx' size='340' side='right'caption='[[1vtx]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1vtx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hadronyche_versuta Hadronyche versuta]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1VTX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1VTX FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1vtx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1vtx OCA], [https://pdbe.org/1vtx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1vtx RCSB], [https://www.ebi.ac.uk/pdbsum/1vtx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1vtx ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/D1A_HADVE D1A_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.<ref>PMID:11171353</ref> <ref>PMID:11874465</ref> <ref>PMID:18986214</ref> <ref>PMID:7816562</ref> <ref>PMID:8281423</ref> <ref>PMID:9028001</ref> <ref>PMID:9845331</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vt/1vtx_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1vtx ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == 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. |
| | | | |
| - | ==About this Structure==
| + | 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<ref>PMID:9384567</ref> |
| - | 1VTX is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Hadronyche_versuta Hadronyche versuta]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1VTX OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9384567 9384567]
| + | </div> |
| | + | <div class="pdbe-citations 1vtx" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Hadronyche versuta]] | | [[Category: Hadronyche versuta]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Chapman, B.E.]] | + | [[Category: Chapman BE]] |
| - | [[Category: Fletcher, J.I.]] | + | [[Category: Fletcher JI]] |
| - | [[Category: King, G.F.]] | + | [[Category: King GF]] |
| - | [[Category: cysteine knot]]
| + | |
| - | [[Category: neurotoxin]]
| + | |
| - | [[Category: sodium channel toxin]]
| + | |
| - | [[Category: venom]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 05:08:04 2007''
| + | |
| Structural highlights
Function
D1A_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
- ↑ 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
- ↑ 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
- ↑ 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, 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
- ↑ 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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