A possible binding site at the extracellular side of the VSD. (A) Top view of a representative snapshot of the interaction between Wu50 and the top-VSD site in the WT Shaker K_V channel. The channel is shown as gray ribbons, the Wu50 compounds are displayed as space filling, each atom type colored differently (black: C or Cl; red: O). Residues are represented as sticks. Residues’ C_α coming in contact with Wu50 in at least one of the channel’s subunits (SUs) during MD simulations are represented as spheres and colored according to the subunit they belong to. (B) Zoomed-in top view of the top-VSD binding site for the WT Shaker K_V channel in the presence of resin-acid derivative Wu50. (C) Contact frequency between any heavy atom of Wu50 and the top-VSD site residues in the WT Shaker K_V channel simulation. For each residue, each bar corresponds to the contact frequency for one of the four subunits, depicted in a different color, following the color scheme presented in Fig. 1. (D and E) Top (D) and side (E) schematic views of the putative effect of resin-acid–derivative binding to the top-VSD site (yellow triangle) The endogenous gating charge arginines (R362 [=R₁], R365 [=R₂], R368 [=R₃], and R372 [=R₄]) are denoted by blue filled or empty circles. The positions of E283 and T326 are denoted by pink and yellow circles, respectively.