6cnu | pdb_00006cnu

Crystal Structure of JzTX-V

spinqualitylabelsall models 6cnu, resolution 1.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: BR, DAL, DAR, DAS, DCY, DGL, DGN, DIL, DLE, DLY, DSN, DTH, DTR, F9D, GOL, LPH, MED, MSE, NH2, SO4 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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