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

Area of Science:

• Biochemistry
• Pharmacology
• Structural Biology

Background:

• Natural toxins from spider venom are potent modulators of ion channels.
• Previously identified spider toxins targeting voltage-gated potassium channels (K_V) primarily inhibit K_V2 and K_V4 subtypes by interacting with voltage-sensing domains.

Purpose of the Study:

• To identify and characterize novel spider-derived toxins targeting voltage-gated potassium channels.
• To investigate the structural basis for the unique pharmacological properties of these toxins.

Main Methods:

• Isolation and sequencing of toxins (murinotoxins MnTx-1 and MnTx-2) from *Pterinochilus murinus* venom.
• Recombinant production and NMR structural determination of MnTx-1.
• Analysis of sequence motifs and three-dimensional structure, including disulfide linkages.

Main Results:

• Discovery of murinotoxins MnTx-1 and MnTx-2, novel spider toxins with selective pore-blocking activity against Shaker-type (K_V1) channels at nanomolar potency.
• Determination of the NMR solution structure of MnTx-1, revealing a unique three-dimensional fold with an alternative disulfide linkage termed the Disulfide-Reined Hairpin (DRH).
• Correlation of the unique DRH structure with the distinct pharmacology of MnTx-1.

Conclusions:

• Novel spider toxins targeting K_V1 channels have been identified.
• The unique Disulfide-Reined Hairpin (DRH) structure of MnTx-1 is responsible for its selective K_V1 channel blockade.
• The DRH motif serves as a promising scaffold for future bioengineering efforts.