BeKm 1

The scorpion toxin BeKm-1 is unique among a variety of known short scorpion toxins affecting potassium channels in its selective action on ether-a-go-go-related gene (ERG)-type channels. BeKm-1 shares the common molecular scaffold with other short scorpion toxins. The toxin spatial structure resolved by NMR consists of a short α-helix and a triple-stranded antiparallel β-sheet. By toxin mutagenesis study we identified the residues that are important for the binding of BeKm-1 to the human ERG K+ (HERG) channel. The most critical residues (Tyr-11, Lys-18, Arg-20, Lys-23) 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. Thus the unique location of the binding site of BeKm-1 provides its specificity toward the HERG channel.   >> Read More

The toxin BeKm-1 isolated from scorpion Buthus eupeus is singled out of other characterized α-KTxs by selectively inhibiting HERG channels, which are voltage-gated K+ channels, coded by the humanether-a-go-go-related gene. The interest in the HERG channels has increased due to the important role these channels play in different tissues, mainly in shaping the action potential in the heart). The HERG channels specify one component of the delayed rectifier that contributes to the repolarization phase of cardiac action potential. One form of inherited long QT syndrome, LQT2, results from genetic defects in herg1 gene and predisposes affected individuals to potentially lethal arrhythmias. However most often the same sickness is derived from the nonspecific blockade of cardiac HERG current by various commonly used medications, such as class III antiarrhythmics, antihistaminics, or antipsychotics. This undesirable side effect is a major hurdle in the development of new and safe drugs, which may be overcome by the resolution of HERG channel pore structure.

New Binding Site on Common Molecular Scaffold Provides HERG Channel Specificity of Scorpion Toxin BeKm-1*210