FIGURE 1.

Molecular architecture of Na_V channels. (A) Topology diagram of mammalian and bacterial Na_V channels in the lipid membrane. Left, mammalian Na_V channels comprise four domains (DI—blue; DII—green; DIII—yellow; DIV—purple) with the fast inactivation gate (red) in the DIII-DIV loop. Right, bacterial Na_V channels contain one domain and lacks the fast inactivation gate. The S4 segments include an array of positive gating charge arginines. (B) Structure of the core Na_V channel domain from bacterial Na_VAb. The 6-TM domain consists of the voltage sensing domain (S1 to S4, light gray) and the pore module (S4 to S5, dark gray) connected by the S4-S5 linker (gold). Between the S5 and S6 segments is the P-loop including the selectivity filter (pink). (C) Structure of the mammalian Na_V α-subunit. Four domains colored as in (A) form a domain-swapped tertiary structure with the pore modules lining the pore architecture at the center, and the VSDs in the periphery.(D) Molecular architecture of the pore. The pore modules form a sodium permeable tunnel (light gray volume). For clarity, only two in-plane domains are illustrated. From top to bottom: the extracellular funnel attracts and concentrates Na⁺ ions; the selectivity filter (pink) selects for passages of hydrated Na⁺ ions; the central cavity contains hydrophobic inner surface; the activation gate formed by the S6 segments provides an iris-like exit. (E) Extracellular view of the selectivity filter superimposed between mammalian and bacterial Na_V channels. Mammalian Na_V channels colored as in (A) contain the DEKA motif to which each domain contributes an amino acid while the bacterial selectivity filter (gray) is symmetric with glutamate residues forming a high-field-strength site. (F) Intracellular view of the activation gate superimposed between mammalian and bacterial Na_V channels. The S6 segments interlace with hydrophobic residues sealing the exit when the channel is closed, and dilating when the channel is open.