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| | ==NMR structure of spider toxin- G7W/N24S mutant of TRTX-Hhn2b== | | ==NMR structure of spider toxin- G7W/N24S mutant of TRTX-Hhn2b== |
| - | <StructureSection load='2mxo' size='340' side='right' caption='[[2mxo]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2mxo' size='340' side='right'caption='[[2mxo]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2mxo]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MXO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MXO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2mxo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Haplopelma_hainanum Haplopelma hainanum]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MXO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MXO FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2mqf|2mqf]]</td></tr> | + | </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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2mxo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mxo OCA], [http://pdbe.org/2mxo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mxo RCSB], [http://www.ebi.ac.uk/pdbsum/2mxo PDBsum]</span></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=2mxo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mxo OCA], [https://pdbe.org/2mxo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mxo RCSB], [https://www.ebi.ac.uk/pdbsum/2mxo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mxo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/H1A03_HAPHA H1A03_HAPHA]] Is a depressant toxin. Blocks the SCN2A/SCN1B (Nav1.2/Beta1) sodium channel receptor (IC(50) is 68 +-6 uM) and the insect sodium channel para/tipE (IC(50) is 4.3 +-0.3 uM), without altering the activation or inactivation kinetics.<ref>PMID:14675784</ref> | + | [https://www.uniprot.org/uniprot/H1A03_CYRHA H1A03_CYRHA] Weakly blocks the rat SCN2A/SCN1B (Nav1.2/beta-1) sodium channel (IC(50)=68 uM) and the insect sodium channel para/tipE (IC(50)=4.3 uM), without altering the activation or inactivation kinetics (depressant toxin).<ref>PMID:14675784</ref> <ref>PMID:26429937</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chin, Y K.Y]] | + | [[Category: Haplopelma hainanum]] |
| - | [[Category: Klint, J K]] | + | [[Category: Large Structures]] |
| - | [[Category: Mobli, M]] | + | [[Category: Chin YKY]] |
| - | [[Category: Nav1 7]] | + | [[Category: Klint JK]] |
| - | [[Category: Spider toxin]] | + | [[Category: Mobli M]] |
| - | [[Category: Toxin]]
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| - | [[Category: Voltage gated ion channel]]
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| Structural highlights
Function
H1A03_CYRHA Weakly blocks the rat SCN2A/SCN1B (Nav1.2/beta-1) sodium channel (IC(50)=68 uM) and the insect sodium channel para/tipE (IC(50)=4.3 uM), without altering the activation or inactivation kinetics (depressant toxin).[1] [2]
Publication Abstract from PubMed
Many spider-venom peptides are known to modulate the activity of the voltage-gated sodium (NaV) subtype 1.7 (NaV1.7) channel, which has emerged as a promising analgesic target. In particular, a class of spider-venom peptides (NaSpTx1) has been found to potently inhibit NaV1.7 (nanomolar IC50), and has been shown to produce analgesic effects in animals. However, one member of this family [micro-TRTX-Hhn2b (Hhn2b)] does not inhibit mammalian NaV channels expressed in dorsal root ganglia at concentrations up to 100 microM. This peptide is classified as a NaSpTx1 member by virtue of its cysteine spacing and sequence conservation over functionally important residues. Here, we have performed detailed structural and functional analyses of Hhn2b, leading us to identify two nonpharmacophore residues that contribute to human NaV1.7 (hNaV1.7) inhibition by nonoverlapping mechanisms. These findings allowed us to produce a double mutant of Hhn2b that shows nanomolar inhibition of hNaV1.7. Traditional structure/function analysis did not provide sufficient resolution to identify the mechanism underlying the observed gain of function. However, by solving the high-resolution structure of both the wild-type and mutant peptides using advanced multidimensional NMR experiments, we were able to uncover a previously unknown network of interactions that stabilize the pharmacophore region of this class of venom peptides. We further monitored the lipid binding properties of the peptides and identified that one of the key amino acid substitutions also selectively modulates the binding of the peptide to anionic lipids. These results will further aid the development of peptide-based analgesics for the treatment of chronic pain.
Rational Engineering Defines a Molecular Switch That Is Essential for Activity of Spider-Venom Peptides against the Analgesics Target NaV1.7.,Klint JK, Chin YK, Mobli M Mol Pharmacol. 2015 Dec;88(6):1002-10. doi: 10.1124/mol.115.100784. Epub 2015 Oct, 1. PMID:26429937[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Li D, Xiao Y, Hu W, Xie J, Bosmans F, Tytgat J, Liang S. Function and solution structure of hainantoxin-I, a novel insect sodium channel inhibitor from the Chinese bird spider Selenocosmia hainana. FEBS Lett. 2003 Dec 18;555(3):616-22. PMID:14675784
- ↑ Klint JK, Chin YK, Mobli M. Rational Engineering Defines a Molecular Switch That Is Essential for Activity of Spider-Venom Peptides against the Analgesics Target NaV1.7. Mol Pharmacol. 2015 Dec;88(6):1002-10. doi: 10.1124/mol.115.100784. Epub 2015 Oct, 1. PMID:26429937 doi:http://dx.doi.org/10.1124/mol.115.100784
- ↑ Klint JK, Chin YK, Mobli M. Rational Engineering Defines a Molecular Switch That Is Essential for Activity of Spider-Venom Peptides against the Analgesics Target NaV1.7. Mol Pharmacol. 2015 Dec;88(6):1002-10. doi: 10.1124/mol.115.100784. Epub 2015 Oct, 1. PMID:26429937 doi:http://dx.doi.org/10.1124/mol.115.100784
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