6cnu
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of JzTX-V== | |
| + | <StructureSection load='6cnu' size='340' side='right' caption='[[6cnu]], [[Resolution|resolution]] 1.05Å' 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> | ||
| + | </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=NH4:AMMONIUM+ION'>NH4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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></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> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:30346167</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 6cnu" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Min, X]] | [[Category: Min, X]] | ||
[[Category: Wang, Z]] | [[Category: Wang, Z]] | ||
| + | [[Category: Inhibitor cysteine knot]] | ||
| + | [[Category: Toxin]] | ||
Revision as of 07:26, 6 March 2019
Crystal Structure of JzTX-V
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