6cgw

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

spinqualitylabelsall models 6cgw Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cgw is a 1 chain structure with sequence from Chilobrachys guangxiensis. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR Ligands: NLE 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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