2m4x

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{{STRUCTURE_2m4x| PDB=2m4x | SCENE= }}
 
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===Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin, Huwentoxin-IV (-TRTX-Hh2a).===
 
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==Function==
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==Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin, Huwentoxin-IV (-TRTX-Hh2a).==
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[[http://www.uniprot.org/uniprot/TXH4_HAPSC 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.<ref>PMID:12228241</ref> <ref>PMID:18628201</ref>
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<StructureSection load='2m4x' size='340' side='right'caption='[[2m4x]]' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2m4x]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Cyriopagopus_schmidti Cyriopagopus schmidti]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2M4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2M4X FirstGlance]. <br>
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</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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2m4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m4x OCA], [https://pdbe.org/2m4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2m4x RCSB], [https://www.ebi.ac.uk/pdbsum/2m4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2m4x ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TXH4_CYRSC TXH4_CYRSC] This lethal neurotoxin (without cyclization at position 53) inhibits neuronal voltage-gated sodium channel Nav1.2/SCN2A (IC(50)=10-150 nM), rNav1.3/SCN3A (IC(50)=338 nM), Nav1.6/SCN8A (IC(50)=117 nM), and hNav1.7/SCN9A (IC(50)=9.6-33 nM) (PubMed:18628201, PubMed:20855463, PubMed:25658507, PubMed:29703751,PubMed:31234412, PubMed:23760503). It inhibits activation of sodium channel by trapping the voltage sensor of domain II (DIIS4) in the closed configuration (PubMed:18628201, PubMed:23760503). The toxin neither shifts the Nav1.7/SCN9A activation curve nor modifies the slope factor (PubMed:20855463). It does not slow fast-inactivation of hNav1.7/SCN9A channels (PubMed:20855463). In addition, it has only a weak affinity for lipid membranes (PubMed:18054060, PubMed:29703751, PubMed:28115115). This toxin also exists with a pyroglutamate at position 53 (PubMed:23826086). The sole difference observed between modified (mHwTx-IV) and unmodified toxins is that moderate or high depolarization voltages (200 mV) permit the unmodified toxin to dissociate, whereas mHwTx-IV toxin does not dissociate, even at high depolarization voltages (PubMed:23826086). These data indicate that mHwTx-IV strongly binds to voltage sensor of sodium channel even at extreme depolarization voltages (PubMed:23826086).<ref>PMID:12228241</ref> <ref>PMID:18054060</ref> <ref>PMID:18628201</ref> <ref>PMID:20855463</ref> <ref>PMID:21659528</ref> <ref>PMID:23523779</ref> <ref>PMID:23760503</ref> <ref>PMID:25658507</ref> <ref>PMID:28115115</ref> <ref>PMID:29483648</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==About this Structure==
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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<ref>PMID:23760503</ref>
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[[2m4x]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Haplopelma_schmidti Haplopelma schmidti]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2M4X OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<references group="xtra"/><references/>
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</div>
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[[Category: Haplopelma schmidti]]
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<div class="pdbe-citations 2m4x" style="background-color:#fffaf0;"></div>
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[[Category: Flinspach, M.]]
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== References ==
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[[Category: Gibbs, A.]]
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<references/>
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[[Category: Toxin]]
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__TOC__
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[[Category: Venom]]
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</StructureSection>
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[[Category: Cyriopagopus schmidti]]
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[[Category: Large Structures]]
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[[Category: Flinspach M]]
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[[Category: Gibbs A]]

Current revision

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

PDB ID 2m4x

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