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5tlr

From Proteopedia

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Current revision

Solution NMR structure of gHwTx-IV

Structural highlights

5tlr is a 1 chain structure with sequence from Cyriopagopus schmidti. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10]

Publication Abstract from PubMed

The human voltage-gated sodium channel sub-type 1.7 (hNaV1.7) is emerging as an attractive target for the development of potent and sub-type selective novel analgesics with increased potency and fewer side effects than existing therapeutics. HwTx-IV, a spider derived peptide toxin, inhibits hNaV1.7 with high potency and is therefore of great interest as an analgesic lead. In the current study we examined whether engineering a HwTx-IV analogue with increased ability to bind to lipid membranes would improve its inhibitory potency at hNaV1.7. This hypothesis was explored by comparing HwTx-IV and two analogues [E1PyrE]HwTx-IV (mHwTx-IV) and [E1G,E4G,F6W,Y30W]HwTx-IV (gHwTx-IV) on their membrane-binding affinity and hNaV1.7 inhibitory potency using a range of biophysical techniques including computational analysis, NMR spectroscopy, surface plasmon resonance, and fluorescence spectroscopy. HwTx-IV and mHwTx-IV exhibited weak affinity for lipid membranes, whereas gHwTx-IV showed improved affinity for the model membranes studied. In addition, activity assays using SH-SY5Y neuroblastoma cells expressing hNaV1.7 showed that gHwTx-IV has increased activity at hNaV1.7 compared to HwTx-IV. Based on these results we hypothesize that an increase in the affinity of HwTx-IV for lipid membranes is accompanied by improved inhibitory potency at hNaV1.7 and that increasing the affinity of gating modifier toxins to lipid bilayers is a strategy that may be useful for improving their potency at hNaV1.7.

Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7.,Agwa AJ, Lawrence N, Deplazes E, Cheneval O, Chen RM, Craik DJ, Schroeder CI, Henriques ST Biochim Biophys Acta. 2017 Jan 20;1859(5):835-844. doi:, 10.1016/j.bbamem.2017.01.020. PMID:28115115^[11]

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, Luo X, Kuang F, Deng M, Wang M, Zeng X, Liang S. Synthesis and characterization of huwentoxin-IV, a neurotoxin inhibiting central neuronal sodium channels. Toxicon. 2008 Feb;51(2):230-9. doi: 10.1016/j.toxicon.2007.09.008. Epub 2007 Sep , 29. PMID:18054060 doi:http://dx.doi.org/10.1016/j.toxicon.2007.09.008
↑ 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
↑ Xiao Y, Blumenthal K, Jackson JO 2nd, Liang S, Cummins TR. The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. Mol Pharmacol. 2010 Dec;78(6):1124-34. doi: 10.1124/mol.110.066332. Epub 2010 Sep, 20. PMID:20855463 doi:http://dx.doi.org/10.1124/mol.110.066332
↑ Xiao Y, Jackson JO 2nd, Liang S, Cummins TR. Common molecular determinants of tarantula huwentoxin-IV inhibition of Na+ channel voltage sensors in domains II and IV. J Biol Chem. 2011 Aug 5;286(31):27301-10. doi: 10.1074/jbc.M111.246876. Epub 2011, Jun 9. PMID:21659528 doi:http://dx.doi.org/10.1074/jbc.M111.246876
↑ Revell JD, Lund PE, Linley JE, Metcalfe J, Burmeister N, Sridharan S, Jones C, Jermutus L, Bednarek MA. Potency optimization of Huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena. Peptides. 2013 Jun;44:40-6. doi: 10.1016/j.peptides.2013.03.011. Epub 2013 Mar, 19. PMID:23523779 doi:http://dx.doi.org/10.1016/j.peptides.2013.03.011
↑ 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
↑ Murray JK, Ligutti J, Liu D, Zou A, Poppe L, Li H, Andrews KL, Moyer BD, McDonough SI, Favreau P, Stocklin R, Miranda LP. Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel. J Med Chem. 2015 Mar 12;58(5):2299-314. doi: 10.1021/jm501765v. Epub 2015 Feb 19. PMID:25658507 doi:http://dx.doi.org/10.1021/jm501765v
↑ Agwa AJ, Lawrence N, Deplazes E, Cheneval O, Chen RM, Craik DJ, Schroeder CI, Henriques ST. Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7. Biochim Biophys Acta. 2017 Jan 20;1859(5):835-844. doi:, 10.1016/j.bbamem.2017.01.020. PMID:28115115 doi:http://dx.doi.org/10.1016/j.bbamem.2017.01.020
↑ Correnti CE, Gewe MM, Mehlin C, Bandaranayake AD, Johnsen WA, Rupert PB, Brusniak MY, Clarke M, Burke SE, De Van Der Schueren W, Pilat K, Turnbaugh SM, May D, Watson A, Chan MK, Bahl CD, Olson JM, Strong RK. Screening, large-scale production and structure-based classification of cystine-dense peptides. Nat Struct Mol Biol. 2018 Mar;25(3):270-278. doi: 10.1038/s41594-018-0033-9. Epub, 2018 Feb 26. PMID:29483648 doi:http://dx.doi.org/10.1038/s41594-018-0033-9
↑ Agwa AJ, Lawrence N, Deplazes E, Cheneval O, Chen RM, Craik DJ, Schroeder CI, Henriques ST. Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7. Biochim Biophys Acta. 2017 Jan 20;1859(5):835-844. doi:, 10.1016/j.bbamem.2017.01.020. PMID:28115115 doi:http://dx.doi.org/10.1016/j.bbamem.2017.01.020

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/5tlr"

Categories: Cyriopagopus schmidti | Large Structures | Agwa AJ | Schroeder CI

@@ Line 1: / Line 1: @@
 ==Solution NMR structure of gHwTx-IV==
-<StructureSection load='5tlr' size='340' side='right' caption='[[5tlr]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='5tlr' size='340' side='right'caption='[[5tlr]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5tlr]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TLR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TLR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5tlr]] 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=5TLR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TLR FirstGlance]. <br>
-</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></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=5tlr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tlr OCA], [http://pdbe.org/5tlr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tlr RCSB], [http://www.ebi.ac.uk/pdbsum/5tlr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tlr ProSAT]</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=5tlr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tlr OCA], [https://pdbe.org/5tlr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tlr RCSB], [https://www.ebi.ac.uk/pdbsum/5tlr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tlr ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Agwa, A J]]
+[[Category: Cyriopagopus schmidti]]
-[[Category: Schroeder, C I]]
+[[Category: Large Structures]]
-[[Category: Disulfide-rich]]
+[[Category: Agwa AJ]]
-[[Category: Sodium channel inhibitor]]
+[[Category: Schroeder CI]]
-[[Category: Spider toxin]]
-[[Category: Toxin]]

5tlr

From Proteopedia

Current revision

Solution NMR structure of gHwTx-IV

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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