5tcz

From Proteopedia

(Difference between revisions)

Current revision

NMR solution structure of engineered Protoxin-II analog

Structural highlights

5tcz is a 1 chain structure with sequence from Thrixopelma pruriens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

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^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM. Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. 2002 Dec 17;41(50):14734-47. PMID:12475222
↑ Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007 Feb;49(2):194-201. Epub 2006 Sep 27. PMID:17087985 doi:http://dx.doi.org/10.1016/j.toxicon.2006.09.014
↑ Smith JJ, Cummins TR, Alphy S, Blumenthal KM. Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation. J Biol Chem. 2007 Apr 27;282(17):12687-97. Epub 2007 Mar 5. PMID:17339321 doi:http://dx.doi.org/10.1074/jbc.M610462200
↑ Sokolov S, Kraus RL, Scheuer T, Catterall WA. Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II. Mol Pharmacol. 2008 Mar;73(3):1020-8. Epub 2007 Dec 21. PMID:18156314 doi:http://dx.doi.org/10.1124/mol.107.041046
↑ Edgerton GB, Blumenthal KM, Hanck DA. Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5. Toxicon. 2008 Sep 1;52(3):489-500. Epub 2008 Jul 9. PMID:18657562 doi:http://dx.doi.org/S0041-0101(08)00401-7
↑ Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008 Nov;74(5):1476-84. doi: 10.1124/mol.108.047670. Epub 2008 Aug, 26. PMID:18728100 doi:http://dx.doi.org/10.1124/mol.108.047670
↑ 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. Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor. Sci Rep. 2017 Jan 3;7:39662. doi: 10.1038/srep39662. PMID:28045073 doi:http://dx.doi.org/10.1038/srep39662

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/5tcz"

Categories: Large Structures | Thrixopelma pruriens | Gibbs AC | Wickenden AD

@@ Line 1: / Line 1: @@
 ==NMR solution structure of engineered Protoxin-II analog==
-<StructureSection load='5tcz' size='340' side='right'caption='[[5tcz]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='5tcz' size='340' side='right'caption='[[5tcz]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5tcz]] is a 1 chain structure. 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 [http://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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5tcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tcz OCA], [http://pdbe.org/5tcz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tcz RCSB], [http://www.ebi.ac.uk/pdbsum/5tcz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tcz ProSAT]</span></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>
 </table>
+== 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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 23: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Gibbs, A C]]
+[[Category: Thrixopelma pruriens]]
-[[Category: Wickenden, A D]]
+[[Category: Gibbs AC]]
-[[Category: Cystine knot]]
+[[Category: Wickenden AD]]
-[[Category: Inhibitor]]
-[[Category: Toxin]]
-[[Category: Venom peptide analog]]

5tcz

From Proteopedia

Current revision

NMR solution structure of engineered Protoxin-II analog

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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