6CNU

Crystal Structure of JzTX-V

Summary for 6CNU

• Entry DOI: 10.2210/pdb6cnu/pdb
• Descriptor: JzTx-V(D), JzTx-V, BROMIDE ION, ... (6 entities in total)
• Functional Keywords: inhibitor cysteine knot, toxin
• Biological source: Chilobrachys guangxiensis (Chinese earth tiger tarantula); More
• Total number of polymer chains: 2
• Total formula weight: 7852.69

Authors

Min, X.,Wang, Z. (deposition date: 2018-03-09, release date: 2019-03-06, Last modification date: 2025-04-02)

Primary citation

Wu, B.,Murray, J.K.,Andrews, K.L.,Sham, K.,Long, J.,Aral, J.,Ligutti, J.,Amagasu, S.,Liu, D.,Zou, A.,Min, X.,Wang, Z.,Ilch, C.P.,Kornecook, T.J.,Lin, M.J.,Be, X.,Miranda, L.P.,Moyer, B.D.,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., 61:9500-9512, 2018

PubMed Abstract: Inhibitors of the voltage-gated sodium channel Na1.7 are being investigated as pain therapeutics due to compelling human genetics. We previously identified Na1.7-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 Na1.7 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 Na1.7-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 Na1.7 inhibitors.

PubMed: 30346167
DOI: 10.1021/acs.jmedchem.8b00736

Experimental method

X-RAY DIFFRACTION (1.05 Å)