Scorpion Neurotoxin BeM9 Derivative Uncovers Unique Interaction Mode with Nav1.5 Sodium Channel Isoform
- 作者: Chernykh M.A.1, Duzheva M.A.1,2, Kuldyushev N.A.1, Peigneur S.3, Berkut A.A.1, Tytgat J.3, Vassilevski A.A.1, Chugunov A.O.1
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隶属关系:
- Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
- D.I. Mendeleev Russian University of Chemical Technology
- KU Leuven, ON II
- 期: 卷 50, 编号 4 (2024)
- 页面: 498-507
- 栏目: Articles
- URL: https://archivog.com/0132-3423/article/view/670848
- DOI: https://doi.org/10.31857/S0132342324040095
- EDN: https://elibrary.ru/MWRFGB
- ID: 670848
如何引用文章
详细
Scorpion α-neurotoxins are classical ligands of voltage-gated sodium channels that inhibit their inactivation. The strength of this effect depends on the organism and channel isoform, and the precise mechanisms explaining the differences in activity are still unknown. Previously, we have shown that scorpion α-toxins are characterized by a modular structure. They consist of a conserved and structurally stable core module and a variable and mobile specificity module, which determines the selectivity for different channels. We noted a higher mobility of the specificity module in toxins active against mammals compared to insect-active toxins. We then hypothesized that the enhanced mobility in mammal toxins was provided by two conserved glycine residues that enclose the N-terminal loop of the specificity module. To test this assumption, we obtained a derivative of the neurotoxin BeM9 from the venom of the scorpion Mesobuthus eupeus with two replacements of amino acid residues in the corresponding positions with glycine (A4G and Y17G). Unexpectedly, it turned out that BeM9GG lost its activity against Nav1.5 channel isoform, characteristic of mammalian cardiac muscle. A comparison of two known structures of voltage-gated sodium channel complexes with scorpion toxins made it possible to explain the observed effect. We hypothesize an essential role of the membrane in the interaction of toxins with the Nav1.5 isoform.
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作者简介
M. Chernykh
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Email: avas@ibch.ru
俄罗斯联邦, ul. Miklukho-Maklaya 16/10, Moscow, 117997
M. Duzheva
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; D.I. Mendeleev Russian University of Chemical Technology
Email: avas@ibch.ru
俄罗斯联邦, ul. Miklukho-Maklaya 16/10, Moscow, 117997; Miusskaya pl. 9, Moscow, 125047
N. Kuldyushev
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Email: avas@ibch.ru
俄罗斯联邦, ul. Miklukho-Maklaya 16/10, Moscow, 117997
S. Peigneur
KU Leuven, ON II
Email: avas@ibch.ru
比利时, Herestraat 49, box 922, 3000, Leuven, Belgium
A. Berkut
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Email: avas@ibch.ru
俄罗斯联邦, ul. Miklukho-Maklaya 16/10, Moscow, 117997
J. Tytgat
KU Leuven, ON II
Email: avas@ibch.ru
比利时, Herestraat 49, box 922, 3000, Leuven
A. Vassilevski
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
编辑信件的主要联系方式.
Email: avas@ibch.ru
俄罗斯联邦, ul. Miklukho-Maklaya 16/10, Moscow, 117997
A. Chugunov
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Email: avas@ibch.ru
俄罗斯联邦, ul. Miklukho-Maklaya 16/10, Moscow, 117997
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