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<p>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<sub>V</sub>) channels inhibit Shab (K<sub>V</sub>2) or Shal-related isoforms (K<sub>V</sub>4) by interacting with their voltage-sensing domains. In this study, we report novel spider-derived pore-blocking toxins that selectively target Shaker-type (K<sub>V</sub>1) channels with nanomolar potency. We isolated murinotoxins MnTx-1 and MnTx-2 from the orange baboon tarantula <i>Pterinochilus murinus</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月8日

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

摘要

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 (KV) channels inhibit Shab (KV2) or Shal-related isoforms (KV4) by interacting with their voltage-sensing domains. In this study, we report novel spider-derived pore-blocking toxins that selectively target Shaker-type (KV1) 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.