BEKM-1

This ERG channel inhibitor (FW = 4091.65 g/mol; CAS 524962-01-4; Soluble to 1 mg/mL in H2O), from the Central Asian scorpion Buthus eupeus, targets human KV11.1 Ether-a-go-go-Related Gene potassium ion currents. BeKm-1 inhibits hERG1 channels (IC50 = 3.3 nM), but has little or no effect, even at 100 nM, on hEAG, hSK1, rSK2, hIK, hBK, KCNQ1/KCNE1, KCNQ2/3, and KCNQ4 channels. BeKm-1 shares a molecular scaffold (consisting of a short a-helix and a triple-stranded antiparallel b-sheet) in common with other short scorpion toxins. Site- directed mutagenesis identified Tyr-11, Lys-18, Arg-20, and Lys-23 as key residues for binding to hERG channels. All four are located in the a-helix and its following loop, whereas the canonical functional site of other short scorpion toxins lies within the b-sheet. BeKm-1 significantly prolongs QTc intervals in isolated rabbit hearts (4.7 at 10 nM, 16.3% at 100 nM), concentrations that inhibit hERG1 channels.