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5tlr
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Solution NMR structure of gHwTx-IV== | |
| + | <StructureSection load='5tlr' size='340' side='right' caption='[[5tlr]], [[NMR_Ensembles_of_Models | 20 NMR models]]' 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> | ||
| + | </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> | ||
| + | <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> | ||
| + | </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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:28115115</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5tlr" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Agwa, A J]] | ||
| + | [[Category: Schroeder, C I]] | ||
| + | [[Category: Disulfide-rich]] | ||
| + | [[Category: Sodium channel inhibitor]] | ||
| + | [[Category: Spider toxin]] | ||
| + | [[Category: Toxin]] | ||
Revision as of 07:26, 9 March 2017
Solution NMR structure of gHwTx-IV
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