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6cgw

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Revision as of 08:57, 11 November 2020

Solution NMR structure of JzTx-V, a Nav 1.7 inhibitory peptide

Structural highlights

6cgw is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[JZTX5_CHIGU] Inhibits tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels (Nav) in rat dorsal root ganglion neurons. Highly inhibits Kv4.2/KCND2 and Kv4.3/KCND3 potassium channels and weakly inhibits Kv2.1/KCNB1 potassium channels. The toxin shifts the activation curves to more depolarized potentials. Also binds to phospholipid membranes.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers.

Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.,Moyer BD, Murray JK, Ligutti J, Andrews K, Favreau P, Jordan JB, Lee JH, Liu D, Long J, Sham K, Shi L, Stocklin R, Wu B, Yin R, Yu V, Zou A, Biswas K, Miranda LP PLoS One. 2018 May 3;13(5):e0196791. doi: 10.1371/journal.pone.0196791., eCollection 2018. PMID:29723257^[5]

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

References

↑ Yuan C, Yang S, Liao Z, Liang S. Effects and mechanism of Chinese tarantula toxins on the Kv2.1 potassium channels. Biochem Biophys Res Commun. 2007 Jan 19;352(3):799-804. Epub 2006 Nov 27. PMID:17150181 doi:http://dx.doi.org/10.1016/j.bbrc.2006.11.086
↑ Zeng X, Deng M, Lin Y, Yuan C, Pi J, Liang S. Isolation and characterization of Jingzhaotoxin-V, a novel neurotoxin from the venom of the spider Chilobrachys jingzhao. Toxicon. 2007 Mar 1;49(3):388-99. doi: 10.1016/j.toxicon.2006.10.012. Epub 2006, Nov 6. PMID:17157888 doi:http://dx.doi.org/10.1016/j.toxicon.2006.10.012
↑ Chen J, Deng M, He Q, Meng E, Jiang L, Liao Z, Rong M, Liang S. Molecular diversity and evolution of cystine knot toxins of the tarantula Chilobrachys jingzhao. Cell Mol Life Sci. 2008 Aug;65(15):2431-44. PMID:18581053 doi:http://dx.doi.org/10.1007/s00018-008-8135-x
↑ Cai LJ, Xu DH, Luo J, Chen RZ, Chi YP, Zeng XZ, Wang XC, Liang SP. [Inhibition of Jingzhaotoxin-V on Kv4.3 channel]. Sheng Li Xue Bao. 2010 Jun 25;62(3):255-60. PMID:20571743
↑ Moyer BD, Murray JK, Ligutti J, Andrews K, Favreau P, Jordan JB, Lee JH, Liu D, Long J, Sham K, Shi L, Stocklin R, Wu B, Yin R, Yu V, Zou A, Biswas K, Miranda LP. Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V. PLoS One. 2018 May 3;13(5):e0196791. doi: 10.1371/journal.pone.0196791., eCollection 2018. PMID:29723257 doi:http://dx.doi.org/10.1371/journal.pone.0196791

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/6cgw"

@@ Line 1: / Line 1: @@
 ==Solution NMR structure of JzTx-V, a Nav 1.7 inhibitory peptide==
-<StructureSection load='6cgw' size='340' side='right' caption='[[6cgw]], [[NMR_Ensembles_of_Models | 8 NMR models]]' scene=''>
+<StructureSection load='6cgw' size='340' side='right'caption='[[6cgw]], [[NMR_Ensembles_of_Models | 8 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6cgw]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CGW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CGW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6cgw]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CGW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CGW FirstGlance]. <br>
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NLE:NORLEUCINE'>NLE</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=6cgw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cgw OCA], [http://pdbe.org/6cgw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cgw RCSB], [http://www.ebi.ac.uk/pdbsum/6cgw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cgw ProSAT]</span></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=6cgw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cgw OCA], [http://pdbe.org/6cgw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cgw RCSB], [http://www.ebi.ac.uk/pdbsum/6cgw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cgw ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Andrews, K]]
 [[Category: Jordan, J B]]

6cgw

From Proteopedia

Revision as of 08:57, 11 November 2020

Solution NMR structure of JzTx-V, a Nav 1.7 inhibitory peptide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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