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Structure and function of hainantoxin-III, a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels isolated from the Chinese bird spider Ornithoctonus hainana.
J Biol Chem. 2013 Jul 12; 288(28):20392-403.JB

Abstract

In the present study, we investigated the structure and function of hainantoxin-III (HNTX-III), a 33-residue polypeptide from the venom of the spider Ornithoctonus hainana. It is a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels. HNTX-III suppressed Nav1.7 current amplitude without significantly altering the activation, inactivation, and repriming kinetics. Short extreme depolarizations partially activated the toxin-bound channel, indicating voltage-dependent inhibition of HNTX-III. HNTX-III increased the deactivation of the Nav1.7 current after extreme depolarizations. The HNTX-III·Nav1.7 complex was gradually dissociated upon prolonged strong depolarizations in a voltage-dependent manner, and the unbound toxin rebound to Nav1.7 after a long repolarization. Moreover, analysis of chimeric channels showed that the DIIS3-S4 linker was critical for HNTX-III binding to Nav1.7. These data are consistent with HNTX-III interacting with Nav1.7 site 4 and trapping the domain II voltage sensor in the closed state. The solution structure of HNTX-III was determined by two-dimensional NMR and shown to possess an inhibitor cystine knot motif. Structural analysis indicated that certain basic, hydrophobic, and aromatic residues mainly localized in the C terminus may constitute an amphiphilic surface potentially involved in HNTX-III binding to Nav1.7. Taken together, our results show that HNTX-III is distinct from β-scorpion toxins and other β-spider toxins in its mechanism of action and binding specificity and affinity. The present findings contribute to our understanding of the mechanism of toxin-sodium channel interaction and provide a useful tool for the investigation of the structure and function of sodium channel isoforms and for the development of analgesics.

Authors+Show Affiliations

College of Life Sciences, Hunan Normal University, Changsha, Hunan, 410081, China. liuzh@hunnu.edu.cnNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

23703613

Citation

Liu, Zhonghua, et al. "Structure and Function of hainantoxin-III, a Selective Antagonist of Neuronal Tetrodotoxin-sensitive Voltage-gated Sodium Channels Isolated From the Chinese Bird Spider Ornithoctonus Hainana." The Journal of Biological Chemistry, vol. 288, no. 28, 2013, pp. 20392-403.
Liu Z, Cai T, Zhu Q, et al. Structure and function of hainantoxin-III, a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels isolated from the Chinese bird spider Ornithoctonus hainana. J Biol Chem. 2013;288(28):20392-403.
Liu, Z., Cai, T., Zhu, Q., Deng, M., Li, J., Zhou, X., Zhang, F., Li, D., Li, J., Liu, Y., Hu, W., & Liang, S. (2013). Structure and function of hainantoxin-III, a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels isolated from the Chinese bird spider Ornithoctonus hainana. The Journal of Biological Chemistry, 288(28), 20392-403. https://doi.org/10.1074/jbc.M112.426627
Liu Z, et al. Structure and Function of hainantoxin-III, a Selective Antagonist of Neuronal Tetrodotoxin-sensitive Voltage-gated Sodium Channels Isolated From the Chinese Bird Spider Ornithoctonus Hainana. J Biol Chem. 2013 Jul 12;288(28):20392-403. PubMed PMID: 23703613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure and function of hainantoxin-III, a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels isolated from the Chinese bird spider Ornithoctonus hainana. AU - Liu,Zhonghua, AU - Cai,Tianfu, AU - Zhu,Qi, AU - Deng,Meichun, AU - Li,Jiayan, AU - Zhou,Xi, AU - Zhang,Fan, AU - Li,Dan, AU - Li,Jing, AU - Liu,Yu, AU - Hu,Weijun, AU - Liang,Songping, Y1 - 2013/05/23/ PY - 2013/5/25/entrez PY - 2013/5/25/pubmed PY - 2013/9/28/medline KW - Inhibitor Cystine Knot Motif KW - NMR KW - Nav1.7 KW - Patch Clamp Electrophysiology KW - Peptides KW - Sodium Channels KW - Spider Venom KW - Toxins SP - 20392 EP - 403 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 288 IS - 28 N2 - In the present study, we investigated the structure and function of hainantoxin-III (HNTX-III), a 33-residue polypeptide from the venom of the spider Ornithoctonus hainana. It is a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels. HNTX-III suppressed Nav1.7 current amplitude without significantly altering the activation, inactivation, and repriming kinetics. Short extreme depolarizations partially activated the toxin-bound channel, indicating voltage-dependent inhibition of HNTX-III. HNTX-III increased the deactivation of the Nav1.7 current after extreme depolarizations. The HNTX-III·Nav1.7 complex was gradually dissociated upon prolonged strong depolarizations in a voltage-dependent manner, and the unbound toxin rebound to Nav1.7 after a long repolarization. Moreover, analysis of chimeric channels showed that the DIIS3-S4 linker was critical for HNTX-III binding to Nav1.7. These data are consistent with HNTX-III interacting with Nav1.7 site 4 and trapping the domain II voltage sensor in the closed state. The solution structure of HNTX-III was determined by two-dimensional NMR and shown to possess an inhibitor cystine knot motif. Structural analysis indicated that certain basic, hydrophobic, and aromatic residues mainly localized in the C terminus may constitute an amphiphilic surface potentially involved in HNTX-III binding to Nav1.7. Taken together, our results show that HNTX-III is distinct from β-scorpion toxins and other β-spider toxins in its mechanism of action and binding specificity and affinity. The present findings contribute to our understanding of the mechanism of toxin-sodium channel interaction and provide a useful tool for the investigation of the structure and function of sodium channel isoforms and for the development of analgesics. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23703613/Structure_and_function_of_hainantoxin_III_a_selective_antagonist_of_neuronal_tetrodotoxin_sensitive_voltage_gated_sodium_channels_isolated_from_the_Chinese_bird_spider_Ornithoctonus_hainana_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=23703613 DB - PRIME DP - Unbound Medicine ER -