Overview of BacNa_v crystal structures. (A) Side view of the Na_vAb channel (Protein Data Bank accession no. 3RVY) with the VSDs colored green, the S4–S5 linkers colored red, and the PM colored blue. The selectivity filter motif in all four subunits is colored yellow. Main regions within the pore structure are indicated, and the front VSD and pore domain are removed for clarity. (B) Voltage-sensor domain from Na_vAb highlights conserved structural and functional features within the VSD including the hydrophobic constriction site (HCS) and the intracellular and extracellular negative charge clusters (INC and ENC). The gating charges (arginine residues, R1–R4) are shown in blue sticks. (Inset) The R2 arginine gating charge hydrogen bonding with a backbone carbonyl from the S3 helix is highlighted. (C) Superposition of the Na_vAb and Na_vRh (Protein Data Bank accession no. 4DXW) channel pores (colored blue and pink, respectively) indicates the possibility of a significant movement of the VSDs within the plane of the membrane. (D) Side-view section of the Na_vAb channel shows locations of bound phospholipids (yellow spheres) within the PM and their penetration through the pore fenestrations. The side chain of Phe203 is shown in pink stick representation for reference, and the closed intracellular activation gate formed by the S6 helices is indicated. (E) Side view sectioned through the PM of Na_vAb shows three coordination sites identified within BacNa_v selectivity filters. From the extracellular to intracellular side, these sites are: Site_HFS, Site_CEN, and Site_IN. The approximate positions of the Thr (T), Leu (L), and Glu (E) backbone or side-chain atoms from the conserved TLESW selectivity motif are also indicated.