6cnu

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of JzTX-V

Structural highlights

6cnu is a 2 chain structure with sequence from Chilobrachys guangxiensis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.05Å
Ligands:	, , , , , , , , , , , , , , , , , , ,
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

Inhibitors of the voltage-gated sodium channel NaV1.7 are being investigated as pain therapeutics due to compelling human genetics. We previously identified NaV1.7-inhibitory peptides GpTx-1 and JzTx-V from tarantula venom screens. Potency and selectivity were modulated through attribute-based positional scans of native residues via chemical synthesis. Herein, we report JzTx-V lead optimization to identify a pharmacodynamically active peptide variant. Molecular docking of peptide ensembles from NMR into a homology model-derived NaV1.7 structure supported prioritization of key residues clustered on a hydrophobic face of the disulfide-rich folded peptide for derivatization. Replacing Trp24 with 5-Br-Trp24 identified lead peptides with activity in electrophysiology assays in engineered and neuronal cells. 5-Br-Trp24 containing peptide AM-6120 was characterized in X-ray crystallography and pharmacokinetic studies and blocked histamine-induced pruritis in mice after subcutaneous administration, demonstrating systemic NaV1.7-dependent pharmacodynamics. Our data suggests a need for high target coverage based on plasma exposure for impacting in vivo end points with selectivity-optimized peptidic NaV1.7 inhibitors.

Discovery of Tarantula Venom-Derived NaV1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis.,Wu B, Murray JK, Andrews KL, Sham K, Long J, Aral J, Ligutti J, Amagasu S, Liu D, Zou A, Min X, Wang Z, Ilch CP, Kornecook TJ, Lin MJ, Be X, Miranda LP, Moyer BD, Biswas K J Med Chem. 2018 Nov 8;61(21):9500-9512. doi: 10.1021/acs.jmedchem.8b00736. Epub , 2018 Oct 22. PMID:30346167^[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
↑ Wu B, Murray JK, Andrews KL, Sham K, Long J, Aral J, Ligutti J, Amagasu S, Liu D, Zou A, Min X, Wang Z, Ilch CP, Kornecook TJ, Lin MJ, Be X, Miranda LP, Moyer BD, Biswas K. Discovery of Tarantula Venom-Derived NaV1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis. J Med Chem. 2018 Nov 8;61(21):9500-9512. doi: 10.1021/acs.jmedchem.8b00736. Epub , 2018 Oct 22. PMID:30346167 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00736

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/6cnu"

Categories: Chilobrachys guangxiensis | Large Structures | Min X | Wang Z

@@ Line 3: / Line 3: @@
 <StructureSection load='6cnu' size='340' side='right'caption='[[6cnu]], [[Resolution|resolution]] 1.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6cnu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CNU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CNU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6cnu]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Chilobrachys_guangxiensis Chilobrachys guangxiensis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CNU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CNU FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.05&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DAR:D-ARGININE'>DAR</scene>, <scene name='pdbligand=DAS:D-ASPARTIC+ACID'>DAS</scene>, <scene name='pdbligand=DCY:D-CYSTEINE'>DCY</scene>, <scene name='pdbligand=DGL:D-GLUTAMIC+ACID'>DGL</scene>, <scene name='pdbligand=DGN:D-GLUTAMINE'>DGN</scene>, <scene name='pdbligand=DIL:D-ISOLEUCINE'>DIL</scene>, <scene name='pdbligand=DLE:D-LEUCINE'>DLE</scene>, <scene name='pdbligand=DLY:D-LYSINE'>DLY</scene>, <scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=DTH:D-THREONINE'>DTH</scene>, <scene name='pdbligand=DTR:D-TRYPTOPHAN'>DTR</scene>, <scene name='pdbligand=F9D:'>F9D</scene>, <scene name='pdbligand=LPH:L-PROPARGYLGLYCINE'>LPH</scene>, <scene name='pdbligand=MED:D-METHIONINE'>MED</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DAR:D-ARGININE'>DAR</scene>, <scene name='pdbligand=DAS:D-ASPARTIC+ACID'>DAS</scene>, <scene name='pdbligand=DCY:D-CYSTEINE'>DCY</scene>, <scene name='pdbligand=DGL:D-GLUTAMIC+ACID'>DGL</scene>, <scene name='pdbligand=DGN:D-GLUTAMINE'>DGN</scene>, <scene name='pdbligand=DIL:D-ISOLEUCINE'>DIL</scene>, <scene name='pdbligand=DLE:D-LEUCINE'>DLE</scene>, <scene name='pdbligand=DLY:D-LYSINE'>DLY</scene>, <scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=DTH:D-THREONINE'>DTH</scene>, <scene name='pdbligand=DTR:D-TRYPTOPHAN'>DTR</scene>, <scene name='pdbligand=F9D:(2~{R})-2-azanylpent-4-ynoic+acid'>F9D</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LPH:L-PROPARGYLGLYCINE'>LPH</scene>, <scene name='pdbligand=MED:D-METHIONINE'>MED</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6cnu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cnu OCA], [http://pdbe.org/6cnu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cnu RCSB], [http://www.ebi.ac.uk/pdbsum/6cnu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cnu 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=6cnu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cnu OCA], [https://pdbe.org/6cnu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cnu RCSB], [https://www.ebi.ac.uk/pdbsum/6cnu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cnu ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/JZTX5_CHIGU 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.<ref>PMID:17150181</ref> <ref>PMID:17157888</ref> <ref>PMID:18581053</ref> <ref>PMID:20571743</ref>
+[https://www.uniprot.org/uniprot/JZTX5_CHIGU 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.<ref>PMID:17150181</ref> <ref>PMID:17157888</ref> <ref>PMID:18581053</ref> <ref>PMID:20571743</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Chilobrachys guangxiensis]]
 [[Category: Large Structures]]
-[[Category: Min, X]]
+[[Category: Min X]]
-[[Category: Wang, Z]]
+[[Category: Wang Z]]
-[[Category: Inhibitor cysteine knot]]
-[[Category: Toxin]]

6cnu

From Proteopedia

Current revision

Crystal Structure of JzTX-V

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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