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Leiurotoxin I (also called scyllatoxin) is a 31-residue toxin which was purified from the venom of the Israeli scorpion Leiurus quinquestriatus hebraeus. In various cell types, it blocks small-conductance Ca2+-activated K+ channels at 10-13-10-11 M concentrations and shows binding specificity and physiological activity similar to the bee venom toxin apamin. Its structure, determined by two-dimensional NMR, presents a helix and a short antiparallel β-sheet stabilized by three disulfide bonds. It is a 31-residue polypeptide cross-linked by three disulfide bridges which are presumably between Cys3-Cys21, Cys8-Cys26, and Cys12-Cys28. Mutational analysis of leiurotoxin I, the structurally homologous PO5 (87% sequence identity), and the biologically related apamin revealed that two positively charged residues play an important role in biological activity. These residues are located in the helical region in all three toxins and are Arg6 and Arg13 for leiurotoxin I, Arg6 and Arg7 for PO5, and Arg13 and Arg14 for apamin.
Mechanism of action
The structure-activity relationships in this group of pharmacologically related toxins, Lei-NH2, P05, and apamin, have been studied using synthetic analogs. These studies suggest that particular positively charged residues (Arg6 and Arg13 for Lei-NH2, Arg6 and Arg7 for P05, Arg13 and Arg14 for apamin) are important for expression of the toxin biological activities. Notably, these residues are located within the α-helical core. Solution structures of several Lei-NH2 and P05 analogs were recently solved by means of 1H-NMR spectroscopy and indicate that the two groups of molecules adopt the same disulfide pairing arrangement (i.e., Cys3-Cys21, Cys8-Cys26, and Cys12-Cys28) with the classical “α/β scorpion fold”. Although the disulfide pairings had not been formerly established for Lei-NH2, they are likely to be organized accordingly.
Application of Leiurotoxin peptides
Polypeptide animal toxins are useful pharmacological probes to study ion-specific channel proteins because they alter channel function by interaction with and modulation of their activities. In the last decade, toxins acting on various types of K+ channels have been isolated from diverse scorpion venoms. Leiurotoxin I (Lei-NH2), it’s a potent blocker of small conductance Ca2+-activated K+ channels (SK channels) in various cell types. The binding and physiological properties of Lei-NH2 are similar to those of the bee venom toxin, apamin (18 residues, two disulfide bridges). However, the sequences of the two toxins are dissimilar. In contrast, scorpion toxin P05 (31 residues, three disulfide bridges), which also possesses Lei-NH2/apamin-like biological properties, is structurally related to Lei-NH2 with 87% sequence identity.
1. Zhu Q, Liang S , Martin L , et al. Role of Disulfide Bonds in Folding and Activity of Leiurotoxin I:? Just Two Disulfides Suffice[J]. Biochemistry, 2002, 41(38):11488-11494.
2. Auguste P, Hugues M , Gravé B, et al. Leiurotoxin I (scyllatoxin), a peptide ligand for Ca2(+)-activated K+ channels. Chemical synthesis, radiolabeling, and receptor characterization.[J]. Journal of Biological Chemistry, 1990, 265(8):4753-4759.
3. Sabatier J M, Lecomte C , Mabrouk K , et al. Synthesis and Characterization of Leiurotoxin I Analogs Lacking One Disulfide Bridge:? Evidence That Disulfide Pairing 3?21 Is Not Required for Full Toxin Activity[J]. Biochemistry, 1996, 35(33):10641-10647.