Introduction
The toxin BeKm 1 is a HERG-specific peptide toxin, which are voltage-gated K+ channels, coded by the human ether-a-go-go-related gene. BeKm 1 was isolated from the venom of the Central Asian Scorpion Buthus eupeus in 1996, and has been shown to block M-like currents from NG108-15 mouse neuroblastoma rat glioma cells and heterologous HERG currents in human embryonic kidney cells and in Xenopus oocytes. BeKm-1 consists of 36 amino acids, including 6 cysteine residues, which form 3 disulfide bridges similar to other scorpion toxins. BeKm-1 shows structural homology to the family of potassium channel blocking scorpion toxins, α-Ktx.
Biological Activity
The specificity of recombinant BeKm 1 has been studied on cloned potassium channels and the HERG was found to be the target of the toxin. BeKm 1 blocks HERG current with a concentration of half-maximal inhibition (IC50) in the low nanomolar range. The residues are important for the binding of BeKm-1 to the HERG channel, and the most critical residues are Tyr-11, Lys-18, Arg-20, Lys-23, which are located in the α-helix and following loop whereas the "traditional" functional site of other short scorpion toxins is formed by residues from the β-sheet. This unique localization of BeKm-1's interaction surface and its specific action on the HERG channel suggest a unique outer mouth structure of the HERG channel. BeKm 1 binds near, but not the HERG pore, which means BeKm-1 does not totally block the K+ flux, and it is possible that BeKm-1-bound HERG channels can conduct currents although with markedly altered voltage-dependence and kinetics of gating.
Function
Human ether-a-go-go-related gene (HERG) encodes the pore-forming subunit of the rapid delayed rectifier K (IKr) channels. IKr plays a key role in maintaining the electrical stability of the heart. HERG is also expressed in noncardiac cell types and may play significant roles under physiological (e.g., insulin secretion in pancreatic β-cells) or pathological conditions. Therefore, agents that can suppress or enhance the HERG channel function may find important therapeutic applications other than antiarrhythmic therapy. BeKm 1 can suppress HERG in the low nM concentration range. Since the positively charged, BeKm-1 is unlikely to cross the plasma membrane easily, it probably does not access its site of action from inside the cell, and as such BeKm 1 may also differ in its state dependence of blockade from other HERG blockers.
References:
1. James T.Milnes, Christopher E.Dempsey, et al. Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Letters, 2003, 547, 20-26.
2. Yuliya V. Korolkova, Eduard V. Bocharov, et al. New Binding Site on Common Molecular Scaffold Provides HERG Channel Specificity of Scorpion Toxin BeKm-1. Journal of Biological Chemistry, 2002, 277 (45), 43104-43109.
3. Mei Zhang, Yuliya V. Korolkova, et al. BeKm-1 Is a HERG-Specific Toxin that Shares the Structure with ChTx but the Mechanism of Action with ErgTx1. Biophysical Journal, 2003, 84, 3022-3036.
4. Kamilla Angelo, Yuliya V. Korolkova, et al. A radiolabeled peptide ligand of the hERG channel, [125I]-BeKm-1. Pflugers Arch-Eur J Physiol, 2003, 447, 55-63.
