Structural basis for the inhibition of voltage-dependent K(+) channel by gating modifier toxin

Voltage-dependent K(+) (K(v)) channels play crucial roles in nerve and muscle action potentials. Voltage-sensing domains (VSDs) of K(v) channels sense changes in the transmembrane potential, regulating the K(+)-permeability across the membrane. Gating modifier toxins, which have been used for the functional analyses of K(v) channels, inhibit K(v) channels by binding to VSD. However, the structural basis for the inhibition remains elusive. Here, fluorescence and NMR analyses of the interaction between VSD derived from K(v)AP channel and its gating modifier toxin, VSTx1, indicate that VSTx1 recognizes VSD under depolarized condition. We identified the VSD-binding residues of VSTx1 and their proximal residues of VSD by the cross-saturation (CS) and amino acid selective CS experiments, which enabled to build a docking model of the complex. These results provide structural basis for the specific binding and inhibition of K(v) channels by gating modifier toxins.