(A) Sequence alignment of CTDs from Nav1.5 and Nav1.4. Identical residues are indicated below the sequence alignment by (*), conservative changes by (:) and semi-conservative changes by (.). Locations of the linker region, EF hand and helix 6 highlighted. The extended region of helix 6 containing sequences implicated in apo- or Ca²⁺-calmodulin binding coloured cyan. Within this region, the consensus IQ-motif is indicated. In the Nav1.5 sequence, examples of LQT3 and BrS-associated residues coloured orange and sky blue, respectively. In the Nav1.4 sequence, myotonia and PMC-associated residues coloured tan and purple, respectively. (B) Comparative structures of CTDs from Nav1.5 (a–c) and Nav1.4 (d,e) with apo-calmodulin (a,d) or Ca²⁺-calmodulin (b,c,e), in side view and top view. To emphasize the variety of ways in which calmodulin can bind to helix 6, the EF hands have been removed from the top views and the orientation of each helix 6 structure has been arbitrarily standardized, with Nav1.5 residue R1897 and its Nav1.4 equivalent K1723 placed at 12 o'clock. In the Nav1.5 structures, LQT3 and BrS-associated residues highlighted as spheres and coloured orange and sky blue, respectively. In the Nav1.4 structures, myotonia and PMC-associated residues highlighted as spheres and coloured tan and purple, respectively. Ca²⁺ ions shown as red balls.