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2m50

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Revision as of 23:09, 9 August 2018

Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin, Huwentoxin-IV (-TRTX-Hh2a).

Structural highlights

2m50 is a 1 chain structure with sequence from Chinese bird spider. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	2m4x
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TXH4_HAPSC] This lethal neurotoxin acts selectively on tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels (Nav), with an IC(50) of 30 nM in rat DRG neurons. Preferentially inhibits neuronal voltage-gated sodium channel subtype hNav1.7/SCN9A (IC(50) is 26 nM), rNav1.2/SCN2A (IC(50) is 150 nM), and rNav1.3/SCN3A (IC(50) is 338 nM), compared with muscle subtypes rNav1.4/SCN4A and hNav1.5/SCN5A (IC(50) is > 10 uM). Inhibits activation of sodium channel by trapping the voltage sensor of domain II of the site 4 in the inward, closed configuration.^[1] ^[2]

Publication Abstract from PubMed

Voltage-gated sodium channels (VGSCs) are essential to the normal function of the vertebrate nervous system. Aberrant function of VGSCs underlies a variety of disorders, including epilepsy, arrhythmia, and pain. A large number of animal toxins target these ion channels and may have significant therapeutic potential. Most of these toxins, however, have not been characterized in detail. Here, by combining patch clamp electrophysiology and radioligand binding studies with peptide mutagenesis, NMR structure determination, and molecular modeling, we have revealed key molecular determinants of the interaction between the tarantula toxin huwentoxin-IV and two VGSC isoforms, Nav1.7 and Nav1.2. Nine huwentoxin-IV residues (F6A, P11A, D14A, L22A, S25A, W30A, K32A, Y33A, and I35A) were important for block of Nav1.7 and Nav1.2. Importantly, molecular dynamics simulations and NMR studies indicated that folding was normal for several key mutants, suggesting that these amino acids probably make specific interactions with sodium channel residues. Additionally, we identified several amino acids (F6A, K18A, R26A, and K27A) that are involved in isoform-specific VGSC interactions. Our structural and functional data were used to model the docking of huwentoxin-IV into the domain II voltage sensor of Nav1.7. The model predicts that a hydrophobic patch composed of Trp-30 and Phe-6, along with the basic Lys-32 residue, docks into a groove formed by the Nav1.7 S1-S2 and S3-S4 loops. These results provide new insight into the structural and molecular basis of sodium channel block by huwentoxin-IV and may provide a basis for the rational design of toxin-based peptides with improved VGSC potency and/or selectivity.

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (mu-TRTX-Hh2a).,Minassian NA, Gibbs A, Shih AY, Liu Y, Neff RA, Sutton SW, Mirzadegan T, Connor J, Fellows R, Husovsky M, Nelson S, Hunter MJ, Flinspach M, Wickenden AD J Biol Chem. 2013 Aug 2;288(31):22707-20. doi: 10.1074/jbc.M113.461392. Epub 2013, Jun 12. PMID:23760503^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Peng K, Shu Q, Liu Z, Liang S. Function and solution structure of huwentoxin-IV, a potent neuronal tetrodotoxin (TTX)-sensitive sodium channel antagonist from Chinese bird spider Selenocosmia huwena. J Biol Chem. 2002 Dec 6;277(49):47564-71. Epub 2002 Sep 11. PMID:12228241 doi:10.1074/jbc.M204063200
↑ Xiao Y, Bingham JP, Zhu W, Moczydlowski E, Liang S, Cummins TR. Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration. J Biol Chem. 2008 Oct 3;283(40):27300-13. doi: 10.1074/jbc.M708447200. Epub 2008 , Jul 14. PMID:18628201 doi:10.1074/jbc.M708447200
↑ Minassian NA, Gibbs A, Shih AY, Liu Y, Neff RA, Sutton SW, Mirzadegan T, Connor J, Fellows R, Husovsky M, Nelson S, Hunter MJ, Flinspach M, Wickenden AD. Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (mu-TRTX-Hh2a). J Biol Chem. 2013 Aug 2;288(31):22707-20. doi: 10.1074/jbc.M113.461392. Epub 2013, Jun 12. PMID:23760503 doi:10.1074/jbc.M113.461392

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2m50"

@@ Line 1: / Line 1: @@
 ==Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin, Huwentoxin-IV (-TRTX-Hh2a).==
 <StructureSection load='2m50' size='340' side='right' caption='[[2m50]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[2m50]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Chinese_bird_spider Chinese bird spider]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2M50 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2M50 FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2m4x|2m4x]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2m50 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m50 OCA], [http://pdbe.org/2m50 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2m50 RCSB], [http://www.ebi.ac.uk/pdbsum/2m50 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2m50 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m50 OCA], [http://pdbe.org/2m50 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2m50 RCSB], [http://www.ebi.ac.uk/pdbsum/2m50 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2m50 ProSAT]</span></td></tr>
 </table>
 == Function ==

2m50

From Proteopedia

Revision as of 23:09, 9 August 2018

Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin, Huwentoxin-IV (-TRTX-Hh2a).

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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