5tcz
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5tcz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Thrixopelma_pruriens Thrixopelma pruriens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TCZ FirstGlance]. <br> | <table><tr><td colspan='2'>[[5tcz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Thrixopelma_pruriens Thrixopelma pruriens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TCZ FirstGlance]. <br> | ||
| - | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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'>[https://proteopedia.org/fgij/fg.htm?mol=5tcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tcz OCA], [https://pdbe.org/5tcz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tcz RCSB], [https://www.ebi.ac.uk/pdbsum/5tcz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tcz 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=5tcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tcz OCA], [https://pdbe.org/5tcz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tcz RCSB], [https://www.ebi.ac.uk/pdbsum/5tcz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tcz ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_THRPR] Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</ref> | [https://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_THRPR] Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain. | ||
| + | |||
| + | Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor.,Flinspach M, Xu Q, Piekarz AD, Fellows R, Hagan R, Gibbs A, Liu Y, Neff RA, Freedman J, Eckert WA, Zhou M, Bonesteel R, Pennington MW, Eddinger KA, Yaksh TL, Hunter M, Swanson RV, Wickenden AD Sci Rep. 2017 Jan 3;7:39662. doi: 10.1038/srep39662. PMID:28045073<ref>PMID:28045073</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5tcz" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
NMR solution structure of engineered Protoxin-II analog
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