IEM mutations in voltage sensors of Na _V 1.7 and Na _V Ab. (A) Topology diagram of Na_V1.7 with four IEM mutations (red circles) in the VS of domains I and II selected for this study (left). Equivalent IEM mutations were introduced into the homotetrameric bacterial channel Na_VAb (cyan) for electrophysiological and structural characterization (right). (B) Structure of human Na_V1.7 with the locations of four IEM mutations mapped onto the model presented in side view (red spheres). Each domain is colored as in A. (C) Structure of Na_VAb with the locations of four IEM mutations mapped onto the model presented in side view (red spheres). For clarity, the IEM mutations are shown only in one subunit (teal). Due to the homotetrameric nature of Na_VAb, the mutations are also present in the remaining subunits (cyan). (D) Structure of human Na_V1.7 with the locations of four IEM mutations mapped onto the model in the top view (red spheres). (E) Structure of Na_VAb (cyan) with the locations of four IEM mutations mapped onto the model in the top view (red spheres). For clarity, the IEM mutations are shown only in one subunit. Due to the homotetrameric nature of Na_VAb, the mutations are also present in the remaining subunits. The structure of Na_V1.7 from D is superimposed (with the IEM mutations shown as pink spheres).