Features of open and closed sodium channels. (a) Overlays of the NavMs (blue), CavAb (orange), and NavAe1 (gray) monomer structures, with black arrows indicating the relative directions of the concerted movements of the VS, S4–S5 linker, S6 pore helix, IM, and top of the CTD when transforming from the open to the closed conformation. (b) Overlays of the complete NavMs (blue) and CavAb (orange) tetrameric structures, showing the overall consequences of the open-to-closed conformational change. The extensions of the S6 helices in NavMs splay the “neck” region of the CTD in the direction of the S4–S5 linker, which then results in a bend angle of nearly 120° at the beginning of the region without canonical secondary structure. This region has been designated the IM of the open state. In the closed CavAb structure, the equivalent “neck” region at the top of the CTD is a helical extension of the narrower opening formed by its S6 helices. As a consequence of the different conformations at the tops of their CTDs, the distal ends of the CavAb CTD (formed of coiled-coils in both structures) protrude into the cytoplasm, further from the membrane interface than they do in NavMs. (c) Enlarged view of the NavMs IM, with the helices depicted in rainbow colored (N- to C-terminal direction) ribbon motif. The regions (S3, S4–S5 linker, S6, and CTD) comprising the IM are labeled in red italics. The side chain and backbone atoms that are involved in the extensive network of hydrogen bonds and ion pairs (dashed lines) are shown in stick motif. The conserved W77 is in purple, and E229 is in cyan.