Cobatoxin

Not to be confused with Cobratoxin.

Cobatoxin is a toxin present in the venom of the scorpion Centruroides noxius. It blocks two potassium channel subtypes; voltage-gated and calcium-activated channels.

Etymology

Coba is a region in Mexico where the Centruroides noxius scorpion is found.

Source

Cobatoxin 1 and 2 are both found in the venom of the Centruroides noxius scorpion.^{[1] [2]}

Chemistry

Structure

Cobatoxin is a 32-residue toxin with 3 disulfide bridges, which are located on C1-C4, C2-C5 and C3- C6 (Cys3-Cys22, Cys8-Cys27, and Cys12-Cys29). The peptide backbone is folded according to an α/β scaffold, both α-helical and two-stranded β-sheet structures are present. Cobatoxin 1 has a rod-like shape due to an extended N-terminus.^[1][2]

Family

Cobatoxin 1 and 2 both belong to the α-KTx family. The α-KTx family is part of the K+-channel-specific scorpion toxins (KTx), which consists of 3 families; α, β, and γ. These 3 families differ in structure.^[3]

Target

Cobatoxin 1 and 2 both block the Kv1.1 K+-channels in mice and the Shaker B K+ channels in insects, which are voltage-dependent K+-channels (Selisko, 1998). Other voltage-dependent K+-channels that are blocked by Cobatoxin 1 are the Kv1.2 K+-channels in rats and Kv1.3 K+-channels in mice. Cobatoxin 1 also blocks the IKCa1 Ca2+-activated K+-channel.^[2]

Mode of action

Cobatoxin 1 is a pore-blocking toxin. The interaction between cobatoxin 1 and the Kv1.2 channel is first esthablished by four salt bridges, which are formed between side chains of the four Kv1.2 α-subunits and amino acids residues of cobatoxin 1. This way a stable complex is formed, named the toxin-ring. Next, a tighter interaction is formed by a hydrophobic interaction between cobatoxin 1 and the α-subunit. Then the Lys21 side chain of cobatoxin 1 blocks the pore by entering the P-domain of the ion channel, which is the selectivity filter.^[2]

Toxicity

The LD₅₀ of cobatoxin 1 after intracerebroventricular injection in mice is 500±45 ng.^[2]

References

1. ^ ^{a b} Selisko B, Garcia C, Becerril B, Gómez-Lagunas F, Garay C, Possani LD (Jun 1998). "Cobatoxins 1 and 2 from Centruroides noxius Hoffmann constitute a subfamily of potassium-channel-blocking scorpion toxins". Eur J Biochem. 254 (3): 468–79. doi:10.1046/j.1432-1327.1998.2540468.x. PMID 9688256. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0014-2956&date=1998&volume=254&issue=3&spage=468. 
2. ^ ^{a b c d e} Jouirou B, Mosbah A, Visan V, et al. (Jan 2004). "Cobatoxin 1 from Centruroides noxius scorpion venom: chemical synthesis, three-dimensional structure in solution, pharmacology and docking on K+ channels". Biochem J. 377 (Pt 1): 37–49. doi:10.1042/BJ20030977. PMC 1223841. PMID 14498829. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1223841. 
3. ^ Tytgat J, Chandy KG, Garcia ML, et al. (Nov 1999). "A unified nomenclature for short-chain peptides isolated from scorpion venoms: alpha-KTx molecular subfamilies". Trends Pharmacol Sci. 20 (11): 444–7. doi:10.1016/S0165-6147(99)01398-X. PMID 10542442. http://linkinghub.elsevier.com/retrieve/pii/S0165-6147(99)01398-X.