Alignments of sequences involved in the IM region. NavMs, domain III of all human Navs, all domains of the human Nav1.7 isoform, and other ion channels (calcium channels [one (Cav2.1) with, one (Cav1.2) without the conserved tryptophan], and the KCNA1 potassium channels) are listed. The locations of the helical regions in the NavMs structure are indicated by the orange bars at the top, and the numbers of the first and last residues of NavMs in each of the segments are noted in italics before/after each segment sequence. The residues of the IM where salt bridges/hydrogen bonds involving side chains are located are noted by the * above the sequence. The colored overlays indicate the conserved tryptophan in S3 (dark purple) and its partner residue (light purple), the E229 in S6 (cyan), and its partner R119 in the linker (light cyan), and for reference, the four VS arginines are in red.