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具有独特折叠结构的蜘蛛毒液肽可选择性阻断Shaker型钾通道。

Spider venom peptides with unique fold selectively block Shaker-type potassium channels.

作者信息

Kuzmenkov Alexey I, Iunusova Valentina A, Lushpa Vladislav A, Deyev Yakov A, Babenko Vladislav V, Osipov Daniil V, Berkut Antonina A, Tytgat Jan, Bocharov Eduard V, Adams David J, Finol-Urdaneta Rocio K, Vassilevski Alexander A

机构信息

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.

Lopukhin Federal Research and Clinical Centre of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russia.

出版信息

Cell Mol Life Sci. 2025 Aug 8;82(1):300. doi: 10.1007/s00018-025-05778-7.

DOI:10.1007/s00018-025-05778-7
PMID:40778948
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12334782/
Abstract

Natural toxins are highly effective at targeting ion channels with high selectivity and potency. To date, all identified spider venom peptide toxins that modulate voltage-gated potassium (K) channels inhibit Shab (K2) or Shal-related isoforms (K4) by interacting with their voltage-sensing domains. In this study, we report novel spider-derived pore-blocking toxins that selectively target Shaker-type (K1) channels with nanomolar potency. We isolated murinotoxins MnTx-1 and MnTx-2 from the orange baboon tarantula Pterinochilus murinus and sequenced them using a combination of Edman degradation, mass spectrometry, and venom gland nanopore transcriptomics. MnTx-1 was produced recombinantly, and its NMR solution structure was determined. Although MnTx-1 shares sequence motifs common to spider toxins, it displays a distinctly different three-dimensional structure, featuring an alternative disulfide linkage, which we have termed the Disulfide-Reined Hairpin (DRH). We attribute the unique pharmacology of MnTx-1 to its unusual spatial structure. The DRH motif represents a promising new miniature scaffold for future bioengineering applications.

摘要

天然毒素在以高选择性和效力靶向离子通道方面非常有效。迄今为止，所有已鉴定的调节电压门控钾（K）通道的蜘蛛毒液肽毒素都是通过与其电压传感结构域相互作用来抑制Shab（K2）或Shal相关亚型（K4）。在本研究中，我们报告了新型的源自蜘蛛的孔道阻断毒素，它们以纳摩尔效力选择性靶向Shaker型（K1）通道。我们从橙色狒狒狼蛛Pterinochilus murinus中分离出了鼠毒素MnTx-1和MnTx-2，并结合埃德曼降解、质谱和毒腺纳米孔转录组学对它们进行了测序。MnTx-1通过重组产生，并确定了其核磁共振溶液结构。尽管MnTx-1具有蜘蛛毒素共有的序列基序，但它呈现出明显不同的三维结构，其特征是一种替代性二硫键连接，我们将其称为二硫键约束发夹（DRH）。我们将MnTx-1独特的药理学特性归因于其不同寻常的空间结构。DRH基序代表了一种有前景的新型微型支架，可用于未来的生物工程应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/2762a8a828a2/18_2025_5778_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/9a56647d793b/18_2025_5778_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/973d6ab7d4eb/18_2025_5778_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/9840f2afefd9/18_2025_5778_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/2762a8a828a2/18_2025_5778_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/9a56647d793b/18_2025_5778_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/973d6ab7d4eb/18_2025_5778_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/9840f2afefd9/18_2025_5778_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/860a/12334782/2762a8a828a2/18_2025_5778_Fig4_HTML.jpg

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本文引用的文献

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Kalium 3.0 is a comprehensive depository of natural, artificial, and labeled polypeptides acting on potassium channels.Kalium 3.0 是一个综合性的天然、人工和标记多肽库，这些多肽作用于钾通道。
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Pmu1a, a novel spider toxin with dual inhibitory activity at pain targets hNa 1.7 and hCa 3 voltage-gated channels.Pmu1a，一种新型蜘蛛毒素，对痛觉靶点 hNa 1.7 和 hCa 3 电压门控通道具有双重抑制活性。
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