Figure 4. BacNa_V PD fenestrations and pharmacology.

(a) Na_VAb PD ³⁷ is shown in surface representation sectioned through the middle. Exemplar side fenestrations are indicated by the arrows. The fenestration “gating” residue (Phe203) is shown as pink sticks. Lipids bound within the central cavity of Na_VAb are shown as cyan spheres and are seen penetrating through the pore fenestrations (arrows). For easy comparison, the Na_VRh PD (PDB 4DXW ³⁹, not shown) was superimposed onto Na_VAb and the bound lipid within the Na_VRh pore is shown as purple and red spheres. Light green background indicates approximate bilayer boundaries. (b) A sectioned view of Na_VAb I217C ³⁷ (left) and Na_VAb WT ³⁸ (right) looking into the central cavity, viewed from below the selectivity filter. Phe203 is shown as pink sticks and select sidechains implicated in drug binding and block in eukaryotic Na_V and Ca_V channels are in space filling color (blue, green and orange). The asymmetric central cavity seen in Na_VAb WT (right) has been suggested to represent a slow inactivated conformation of the pore, where a reshaping of the pore fenestrations and putative drug binding sites are seen. (c) Homology model of human Na_V1.7 based on the Na_VAb (PDB 3RVY). Left: select residues implicated in local anesthetic block in DIV S6 of Na_V channels (Phe1764 green and Tyr1771 orange) and a residue implicated in DHP block in DIII S6 of rat Ca_V1.2 (accession: P22002; Met1187 blue) illustrate a potential composite drug receptor site within the central cavity of eukaryotic Na_V and Ca_V channels. Right: sequence conservation analysis for all human Na_V channels (Na_V1.1- Na_V1.9) is mapped onto the Na_V1.7 homology model and demonstrate regions of high and low conservation in and around the central cavity.