Hemitoxin, the first potassium channel toxin from the venom of the Iranian scorpionHemiscorpius lepturus

Abstract

Hemitoxin (HTX) is a new K+ channel blocker isolated from the venom of the Iranian scorpion Hemiscorpius lepturus. It represents only 0.1% of the venom proteins, and displaces [125I]α‐dendrotoxin from its site on rat brain synaptosomes with an IC50 value of 16 nm. The amino acid sequence of HTX shows that it is a 35‐mer basic peptide with eight cysteine residues, sharing 29–69% sequence identity with other K+ channel toxins, especially with those of the αKTX6 family. A homology‐based molecular model generated for HTX shows the characteristic α/β‐scaffold of scorpion toxins. The pairing of its disulfide bridges, deduced from MS of trypsin‐digested peptide, is similar to that of classical four disulfide bridged scorpion toxins (Cys1–Cys5, Cys2–Cys6, Cys3–Cys7 and Cys4–Cys8). Although it shows the highest sequence similarity with maurotoxin, HTX displays different affinities for Kv1 channel subtypes. It blocks rat Kv1.1, Kv1.2 and Kv1.3 channels expressed in Xenopus oocytes with IC50 values of 13, 16 and 2 nm, respectively. As previous studies have shown the critical role played by the β‐sheet in Kv1.3 blockers, we suggest that Arg231 is also important for Kv1.3 versus Kv1.2 HTX positive discrimination. This article gives information on the structure–function relationships of Kv1.2 and Kv1.3 inhibitors targeting developing peptidic inhibitors for the rational design of new toxins targeting given K+ channels with high selectivity.

Characteristics and Lethality of a Novel Recombinant Dermonecrotic Venom Phospholipase D from Hemiscorpius lepturus

“…H. lepturus venom is very toxic and some of its peptide and protein components have been completely or partially characterized, such as Hemitoxin [29], Hemicalcin [6], Heminecrolysin [27] and Hemilipin [30]. …”

A camelid antibody candidate for development of a therapeutic agent against Hemiscorpius lepturus envenomation

“…HTX is a potassium channel inhibitor isolated from Iranian H. lepturus venom. The structure and function relationships between K + channel blocker subtypes for HTX allowed a rational design of a new K + channel blocker drug (4). HCa has also been identified as a new toxin from Iranian H. lepturus venom that is active on ryanodinesensitive Ca 2+ channels where it induces Ca 2+ release from vesicles.…”

“…The venom of H. lepturus is very toxic; it includes many components, such as hemicalcin (HCa), hemitoxin (HTX), and heminecrolysin (HNc) (2, 3). HTX is a potassium channel blocker (4), HCa affects calcium channels and is cytotoxic in mice (5), and HNc is a 33 kDa protein with a hemolytic effect on red blood cells (RBCs) (3).…”

Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi

“…Nonetheless, it would be desirable to confirm experimentally the disulfide bridge pattern of urotoxin. The need for experimental confirmation is underlined by the discrepancy of the 3D model of hemitoxin, which suggested an unusual disulfide bridging pattern, compared with the experimental data that showed a conventional one (Srairi-Abid et al, 2008). The nonconventional disulfide pairing seems to be important for high-affinity binding of maurotoxin to rat K v 1.2 channels.…”