Unusual binding mode of scorpion toxin BmKTX onto potassium channels relies on its distribution of acidic residues

Abstract Besides classical scorpion toxin–potassium channel binding modes, novel modes remain unknown. Here, we report a novel binding mode of native toxin BmKTX towards Kv1.3 channel. The combined experimental and computational data indicated that BmKTX-D33H analog used the classical anti-parallel β-sheet domain as the channel-interacting interface together with the conserved channel pore-blocking Lys 26 . However, the wild-type BmKTX was found to use Arg 23 rather than Lys 26 as the new pore-blocking residue, and mainly adopt the turn motif between the α-helix and antiparallel β-sheet domains to recognize K v 1.3 channel. Together, these findings not only reveal that scorpion toxin–potassium channel interaction modes are more diverse than thought, but also highlight the functional role of toxin acidic residues in mediating diverse toxin–potassium channel binding modes.