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2mqf

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NMR structure of spider toxin-TRTX-Hhn2b

Structural highlights

2mqf is a 1 chain structure with sequence from Haplopelma hainanum. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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/2mqf"

Categories: Haplopelma hainanum | Large Structures | Chin YKY | Klint JK | Mobli M

@@ Line 1: / Line 1: @@
 ==NMR structure of spider toxin-TRTX-Hhn2b==
-<StructureSection load='2mqf' size='340' side='right' caption='[[2mqf]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2mqf' size='340' side='right'caption='[[2mqf]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2mqf]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MQF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MQF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2mqf]] 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=2MQF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MQF FirstGlance]. <br>
-</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=2mqf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mqf OCA], [http://pdbe.org/2mqf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mqf RCSB], [http://www.ebi.ac.uk/pdbsum/2mqf PDBsum]</span></td></tr>
+</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=2mqf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mqf OCA], [https://pdbe.org/2mqf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mqf RCSB], [https://www.ebi.ac.uk/pdbsum/2mqf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mqf ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 21: @@
 __TOC__
 </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]]
-[[Category: Voltage gated ion channel]]

2mqf

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Current revision

NMR structure of spider toxin-TRTX-Hhn2b

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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