Spider venom peptides with unique fold selectively block Shaker-type potassium channels
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 (KV) channels inhibit Shab (KV2) or Shal-related isoforms (KV4) by interacting with their voltage-sensin...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer
2025-08-01
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| Series: | Cellular and Molecular Life Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s00018-025-05778-7 |
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| Summary: | 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 (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. |
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| ISSN: | 1420-9071 |