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Synthesis and biological characterization of synthetic analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a neuronal tetrodotoxin-sensitive sodium channel inhibitor.
Toxicon. 2013 Sep; 71:57-65.T

Abstract

Huwentoxin-IV (HWTX-IV, also named Mu-theraphotoxin-Hh2a) is a typical inhibitor cystine knot peptide isolated from the venom of Chinese tarantula Ornithoctonus huwena and is found to inhibit tetrodotoxin-sensitive (TTX-S) sodium channels from mammalian sensory neurons. This peptide binds to neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II in neuronal sodium channels. However, the molecular surface of HWTX-IV interaction with sodium channels remains unknown. In this study, we synthesized HWTX-IV and three mutants (T28D, R29A and Q34D) and characterized their functions on TTX-S sodium channels from adult rat dorsal root ganglion (DRG) neurons. Analysis of liquid chromatography, mass spectrometry and circular dichroism spectrum indicated that all four synthetic peptides are properly folded. Synthetic HWTX-IV exhibited the same activity as native HWTX-IV, while three mutations reduced toxin binding affinities by 10-200 fold, indicating that the basic or vicinal polar residues Thr²⁸, Arg²⁹, and Gln³⁴ in C-terminus might play critical roles in the interaction of HWTX-IV with TTX-S sodium channels.

Authors+Show Affiliations

Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China. dengmch@csu.edu.cnNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23726857

Citation

Deng, Meichun, et al. "Synthesis and Biological Characterization of Synthetic Analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a Neuronal Tetrodotoxin-sensitive Sodium Channel Inhibitor." Toxicon : Official Journal of the International Society On Toxinology, vol. 71, 2013, pp. 57-65.
Deng M, Luo X, Jiang L, et al. Synthesis and biological characterization of synthetic analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a neuronal tetrodotoxin-sensitive sodium channel inhibitor. Toxicon. 2013;71:57-65.
Deng, M., Luo, X., Jiang, L., Chen, H., Wang, J., He, H., & Liang, S. (2013). Synthesis and biological characterization of synthetic analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a neuronal tetrodotoxin-sensitive sodium channel inhibitor. Toxicon : Official Journal of the International Society On Toxinology, 71, 57-65. https://doi.org/10.1016/j.toxicon.2013.05.015
Deng M, et al. Synthesis and Biological Characterization of Synthetic Analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a Neuronal Tetrodotoxin-sensitive Sodium Channel Inhibitor. Toxicon. 2013;71:57-65. PubMed PMID: 23726857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and biological characterization of synthetic analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a neuronal tetrodotoxin-sensitive sodium channel inhibitor. AU - Deng,Meichun, AU - Luo,Xuan, AU - Jiang,Liping, AU - Chen,Hanchun, AU - Wang,Jun, AU - He,Hailun, AU - Liang,Songping, Y1 - 2013/05/29/ PY - 2013/02/27/received PY - 2013/05/12/revised PY - 2013/05/15/accepted PY - 2013/6/4/entrez PY - 2013/6/4/pubmed PY - 2014/2/12/medline KW - DRG KW - Dorsal root ganglion KW - HPLC KW - HWTX KW - HWTX-IV KW - High pressure liquid chromatography KW - Huwentoxin KW - IC(50) KW - ICK KW - Inhibitor cystine knot KW - Kv channel KW - MALDI-TOF KW - Matrix assisted laser desorption/ionization time-of-flight KW - Median inhibitory concentration KW - Mutant KW - Patch-clamp KW - Protein folding KW - Solid-phase peptide synthesis KW - TTX KW - TTX-R KW - TTX-S KW - TTX-resistant KW - TTX-sensitive KW - Tetrodotoxin KW - VGSC KW - Voltage-gated potassium channel KW - Voltage-gated sodium channel SP - 57 EP - 65 JF - Toxicon : official journal of the International Society on Toxinology JO - Toxicon VL - 71 N2 - Huwentoxin-IV (HWTX-IV, also named Mu-theraphotoxin-Hh2a) is a typical inhibitor cystine knot peptide isolated from the venom of Chinese tarantula Ornithoctonus huwena and is found to inhibit tetrodotoxin-sensitive (TTX-S) sodium channels from mammalian sensory neurons. This peptide binds to neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II in neuronal sodium channels. However, the molecular surface of HWTX-IV interaction with sodium channels remains unknown. In this study, we synthesized HWTX-IV and three mutants (T28D, R29A and Q34D) and characterized their functions on TTX-S sodium channels from adult rat dorsal root ganglion (DRG) neurons. Analysis of liquid chromatography, mass spectrometry and circular dichroism spectrum indicated that all four synthetic peptides are properly folded. Synthetic HWTX-IV exhibited the same activity as native HWTX-IV, while three mutations reduced toxin binding affinities by 10-200 fold, indicating that the basic or vicinal polar residues Thr²⁸, Arg²⁹, and Gln³⁴ in C-terminus might play critical roles in the interaction of HWTX-IV with TTX-S sodium channels. SN - 1879-3150 UR - https://www.unboundmedicine.com/medline/citation/23726857/Synthesis_and_biological_characterization_of_synthetic_analogs_of_Huwentoxin_IV__Mu_theraphotoxin_Hh2a__a_neuronal_tetrodotoxin_sensitive_sodium_channel_inhibitor_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-0101(13)00196-7 DB - PRIME DP - Unbound Medicine ER -