Mapping the mutations that perturb allosteric modification by lidocaine. (A) Surface representation of the Nav1.4 sodium channel model with mutations that disrupt the communication between the lidocaine-binding site and voltage sensor, viewed from the intracellular side. A color gradient from yellow to red was used to represent ΔV_1/2 changes induced upon the addition of lidocaine. (B) Same as in A after the structure was rotated by 90°. The domains I and IV are hidden from view by the other two domains. (C) Surface representation of domain III of the Nav1.4 channel. The other three domains were removed for clarity. The residues were color-coded as in A. (D) A close-up view of the S4–S5 linker, N terminus of S5, and C terminus of S6, with transparent surfaces and side chains colored as in A. All of these structures were drawn using PyMol (DeLano Scientific LLC).