Fig 6.

(A) Sequence alignment of sodium channel segments involved in the proposed mechanism by which mutation T^1520/3i(-1)I allosterically induces small changes in the PyR1 site geometry. Highlighted are residues (except position 2i18), which are shown in panels B and C. Residue numbers in NavPaS and EeNav1.4 are sequential numbers in the PDB files of the cryo-EM structures where some segments are lacking. (B) and (C), Cryo-EM structures of eukaryotic sodium channels NavPaS (B) and EeNav1.4 (C). The pore-module helices in repeats I, II, III, and IV are magenta, yellow, green and gray, respectively. Side chains in positions 2i18 and 3i13, which correspond to AaNa_v1-1 residues 1016 and 1534, are space-filled. In both channels, these residues are in the II/III repeat interface that harbors the pyrethroid receptor site PyR1. Threonine T^3(i-1) in the extracellular loop of NavPaS, which correspond to T^1520/3(i-1) in AaNa_v1-1, is close to the N-terminus of IIIS6 and in AaNa_v1-1 it cannot directly interact with PyR1-bound pyrethroids.