6CHC

JzTx-V toxin peptide, wild-type

6CHC の概要

• エントリーDOI: 10.2210/pdb6chc/pdb
• NMR情報: BMRB: 30413
• 分子名称: Beta/kappa-theraphotoxin-Cg2a (1 entity in total)
• 機能のキーワード: jztx-v wild type peptide toxin, toxin
• 由来する生物種: Chilobrachys guangxiensis (Chinese earth tiger tarantula)
• 細胞内の位置: Secreted : Q2PAY4
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 3758.60

構造登録者

Jordan, J.B. (登録日: 2018-02-22, 公開日: 2018-05-16, 最終更新日: 2024-10-23)

主引用文献

Moyer, B.D.,Murray, J.K.,Ligutti, J.,Andrews, K.,Favreau, P.,Jordan, J.B.,Lee, J.H.,Liu, D.,Long, J.,Sham, K.,Shi, L.,Stocklin, R.,Wu, B.,Yin, R.,Yu, V.,Zou, A.,Biswas, K.,Miranda, L.P.
Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.
PLoS ONE, 13:e0196791-e0196791, 2018

PubMed Abstract: 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.

PubMed: 29723257
DOI: 10.1371/journal.pone.0196791

実験手法

SOLUTION NMR