Abstract
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 alpha-helix and a triple-stranded antiparallel beta-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 alpha-helix and following loop whereas the "traditional" functional site of other short scorpion toxins is formed by residues from the beta-sheet. Thus the unique location of the binding site of BeKm-1 provides its specificity toward the HERG channel.
Highlights
Functional properties of various proteins are frequently associated with structural domains adopting distinct spatial organization
By toxin mutagenesis study we identified the residues that are important for the binding of BeKm-1 to the human ether-a-go-go-related gene (ERG) K؉ (HERG) channel
The toxin BeKm-1 isolated from scorpion Buthus eupeus is singled out of other characterized ␣-KTxs by selectively inhibiting HERG channels [5], which are voltage-gated Kϩ channels, coded by the human ether-a-go-go-related gene
Summary
Functional properties of various proteins are frequently associated with structural domains adopting distinct spatial organization. Our earlier studies [5] showed that substitutions of Arg-27 and Phe-32 for lysines in the BeKm-1, corresponding to the most conserved amino acid residues of potassium channel blockers from scorpion venoms [2], do not dramatically affect toxin binding with the HERG channel.
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