Charybdotoxin
Charybdotoxin is a 37-amino acid scorpion venom peptide that blocks intermediate- and large-conductance calcium-activated potassium channels, used extensively in ion channel research.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C176H277N51O55S7 |
| Molecular Weight | 4295.85 g/mol |
| CAS Number | 95509-19-2 |
| IUPAC Name | Charybdotoxin (Leiurus quinquestriatus) |
| Peptide Class | Scorpion Neurotoxin (K+ Channel Blocker) |
| Origin | Leiurus quinquestriatus (deathstalker) |
| Disulfide Bonds | 3 (ICK motif) |
Structure
Charybdotoxin (ChTX) is a 37-amino acid peptide from the venom of the deathstalker scorpion (Leiurus quinquestriatus hebraeus). It belongs to the short-chain scorpion toxin superfamily with three intramolecular disulfide bonds forming an inhibitor cysteine knot (ICK) motif. The peptide has a net positive charge (+5) and a well-defined surface-exposed dyad of lysine and tyrosine residues critical for channel binding.
Mechanism of Action
Charybdotoxin blocks calcium-activated potassium channels (KCa) by binding to the external pore:
- IKCa channels (KCa3.1): Intermediate-conductance channels blocked at nanomolar concentrations
- BK channels (KCa1.1): Large-conductance (maxi-K) channels blocked at low nanomolar concentrations
- Voltage-gated K+ channels: Some Kv channels (Kv1.2, Kv1.3) also sensitive
The toxin physically occludes the channel pore from the extracellular side, preventing potassium efflux. A single lysine residue (Lys27) inserts into the selectivity filter, mimicking a hydrated potassium ion.
Biological Functions
Charybdotoxin is a venom component for prey immobilization:
- Neurotoxicity: Blockade of KCa channels causes repetitive neuronal firing and convulsions
- Smooth muscle effects: BK channel blockade increases vascular and airway smooth muscle tone
- Immune modulation: IKCa channel blockade affects T cell activation
Research and Clinical Applications
Charybdotoxin is primarily a research tool:
- Ion channel characterization: Defining KCa channel subtypes and their physiological roles
- Drug development: Selectivity profiles guide development of KCa channel modulators for autoimmune disease (KCa3.1 inhibitors) and epilepsy (BK channel modulators)
- Structural biology: High-resolution structures of ChTX-channel complexes reveal pore architecture
No approved therapeutic uses, but KCa3.1 inhibitors derived from charybdotoxin pharmacophore are in clinical development for sickle cell disease and autoimmune disorders.
Safety and Side Effects
Charybdotoxin is neurotoxic when injected systemically, causing convulsions and death in animal models. The peptide is not absorbed through intact skin. Envenomation by Leiurus scorpions causes local pain, autonomic dysfunction, and cardiovascular effects. Research use requires standard laboratory safety precautions.
References
- Miller, C., et al. (1985). Charybdotoxin, a protein inhibitor of single Ca2+-activated K+ channels. Nature, 313, 316-318.
- Bhatt, D.L., et al. (2013). Structural basis for charybdotoxin binding to BK channels. Proceedings of the National Academy of Sciences, 110, 15559-15564.
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