The scorpion toxin BeKm‐1 blocks hERG cardiac potassium channels using an indispensable arginine residue

BeKm‐1 is a peptide toxin from scorpion venom that blocks the pore of the potassium channel hERG (Kv11.1) in the human heart. Although individual protein structures have been resolved, the structure of the complex between hERG and BeKm‐1 is unknown. Here, we used molecular dynamics and ensemble docking, guided by previous double‐mutant cycle analysis data, to obtain an in silico model of the hERG–BeKm‐1 complex. Adding to the previous mutagenesis study of BeKm‐1, our model uncovers the key role of residue Arg20, which forms three interactions (a salt bridge and hydrogen bonds) with the channel vestibule simultaneously. Replacement of this residue even by lysine weakens the interactions significantly. In accordance, the recombinantly produced BeKm‐1R20K mutant exhibited dramatically decreased activity on hERG. Our model may be useful for future drug design attempts. Using computational methods, we constructed a model of the cardiac ion channel hERG in complex with BeKm‐1, a scorpion toxin. We identified the crucial role of the toxin residue Arg20 and validated it by in silico and in vitro mutagenesis. The BeKm‐1R20K mutant showed dramatically reduced activity, suggesting the significance of Arg20 for channel binding. Our model aids future drug design attempts.