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Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels.
Peptides. 2015 Jun; 68:148-56.P

Abstract

Peptide toxins often have pharmacological applications and are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a group of potential VGSC inhibitors have been reported from tarantula venoms, little is known about the mechanism of their interaction with VGSCs. In this study, we showed that hainantoxin-IV (β-TRTX-Hn2a, HNTX-IV in brief), a 35-residue peptide from Ornithoctonus hainana venom, preferentially inhibited rNav1.2, rNav1.3 and hNav1.7 compared with rNav1.4 and hNav1.5. hNav1.7 was the most sensitive to HNTX-IV (IC50∼21nM). In contrast to many other tarantula toxins that affect VGSCs, HNTX-IV at subsaturating concentrations did not alter activation and inactivation kinetics in the physiological range of voltages, while very large depolarization above +70mV could partially activate toxin-bound hNav1.7 channel, indicating that HNTX-IV acts as a gating modifier rather than a pore blocker. Site-directed mutagenesis indicated that the toxin bound to site 4, which was located on the extracellular S3-S4 linker of hNav1.7 domain II. Mutants E753Q, D816N and E818Q of hNav1.7 decreased toxin affinity for hNav1.7 by 2.0-, 3.3- and 130-fold, respectively. In silico docking indicated that a three-toed claw substructure formed by residues with close contacts in the interface between HNTX-IV and hNav1.7 domain II stabilized the toxin-channel complex, impeding movement of the domain II voltage sensor and inhibiting hNav1.7 activation. Our data provide structural details for structure-based drug design and a useful template for the design of highly selective inhibitors of a specific subtype of VGSCs.

Authors+Show Affiliations

College of Life Sciences, Hunan Normal University, Changsha, 410081 Hunan, China.College of Life Sciences, Hunan Normal University, Changsha, 410081 Hunan, China.Research Center of Biological Information, College of Science, National University of Defense Technology, Changsha, 410073 Hunan, China.Key Laboratory of Molecular Biophysics, Huazhong University of Science and Technology, Ministry of Education, College of Life Science and Technology, Wuhan, Hubei 430074, China.College of Life Sciences, Hunan Normal University, Changsha, 410081 Hunan, China.Key Laboratory of Molecular Biophysics, Huazhong University of Science and Technology, Ministry of Education, College of Life Science and Technology, Wuhan, Hubei 430074, China. Electronic address: shengwang@hust.edu.cn.College of Life Sciences, Hunan Normal University, Changsha, 410081 Hunan, China. Electronic address: liuzh@hunnu.edu.cn.

Pub Type(s)

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

Language

eng

PubMed ID

25218973

Citation

Cai, Tianfu, et al. "Mapping the Interaction Site for the Tarantula Toxin hainantoxin-IV (β-TRTX-Hn2a) in the Voltage Sensor Module of Domain II of Voltage-gated Sodium Channels." Peptides, vol. 68, 2015, pp. 148-56.
Cai T, Luo J, Meng E, et al. Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels. Peptides. 2015;68:148-56.
Cai, T., Luo, J., Meng, E., Ding, J., Liang, S., Wang, S., & Liu, Z. (2015). Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels. Peptides, 68, 148-56. https://doi.org/10.1016/j.peptides.2014.09.005
Cai T, et al. Mapping the Interaction Site for the Tarantula Toxin hainantoxin-IV (β-TRTX-Hn2a) in the Voltage Sensor Module of Domain II of Voltage-gated Sodium Channels. Peptides. 2015;68:148-56. PubMed PMID: 25218973.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels. AU - Cai,Tianfu, AU - Luo,Ji, AU - Meng,Er, AU - Ding,Jiuping, AU - Liang,Songping, AU - Wang,Sheng, AU - Liu,Zhonghua, Y1 - 2014/09/10/ PY - 2014/08/01/received PY - 2014/09/01/revised PY - 2014/09/02/accepted PY - 2014/9/15/entrez PY - 2014/9/15/pubmed PY - 2016/3/2/medline KW - Nav1.7 KW - Tarantula toxin KW - VGSCs KW - Voltage sensor SP - 148 EP - 56 JF - Peptides JO - Peptides VL - 68 N2 - Peptide toxins often have pharmacological applications and are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a group of potential VGSC inhibitors have been reported from tarantula venoms, little is known about the mechanism of their interaction with VGSCs. In this study, we showed that hainantoxin-IV (β-TRTX-Hn2a, HNTX-IV in brief), a 35-residue peptide from Ornithoctonus hainana venom, preferentially inhibited rNav1.2, rNav1.3 and hNav1.7 compared with rNav1.4 and hNav1.5. hNav1.7 was the most sensitive to HNTX-IV (IC50∼21nM). In contrast to many other tarantula toxins that affect VGSCs, HNTX-IV at subsaturating concentrations did not alter activation and inactivation kinetics in the physiological range of voltages, while very large depolarization above +70mV could partially activate toxin-bound hNav1.7 channel, indicating that HNTX-IV acts as a gating modifier rather than a pore blocker. Site-directed mutagenesis indicated that the toxin bound to site 4, which was located on the extracellular S3-S4 linker of hNav1.7 domain II. Mutants E753Q, D816N and E818Q of hNav1.7 decreased toxin affinity for hNav1.7 by 2.0-, 3.3- and 130-fold, respectively. In silico docking indicated that a three-toed claw substructure formed by residues with close contacts in the interface between HNTX-IV and hNav1.7 domain II stabilized the toxin-channel complex, impeding movement of the domain II voltage sensor and inhibiting hNav1.7 activation. Our data provide structural details for structure-based drug design and a useful template for the design of highly selective inhibitors of a specific subtype of VGSCs. SN - 1873-5169 UR - https://www.unboundmedicine.com/medline/citation/25218973/Mapping_the_interaction_site_for_the_tarantula_toxin_hainantoxin_IV__β_TRTX_Hn2a__in_the_voltage_sensor_module_of_domain_II_of_voltage_gated_sodium_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0196-9781(14)00273-3 DB - PRIME DP - Unbound Medicine ER -