FIGURE 6.

Putative druggable sites on Na_V channels. (A) The hydrophobic surface between the VSD and the pore of rat Na_V1.5 channel interacts with lipids in the membrane. Lipid and ligand molecules are illustrated as cyan sticks overlaid with semi-transparent van der Waals spheres. Class IC anti-arrhythmic drug flecainide can be seen through the fenestration window into the pore. Tight binding of lipids suggests possible druggable sites on the lipid face of Na_V channels. (B) Putative druggable site at the level of the outer membrane leaflet near the P-loop. Amlodipine DHP binds to engineered calcium channel Ca_VAb at the inter-subunit crevice formed by neighboring S6 helices and the P-helix to trigger allosteric changes at the selectivity filter. (C) Putative druggable site at the level of the inner membrane leaflet near the S4-S5 linker. Resiniferatoxin (RTX) binds in the vanilloid pocket formed by residues from S3 and S4 in the VSD, the S4-S5 linker, and S5 and S6 of the pore, and displace resident phospholipid in this pocket to activate TRPV1 channel. (D) Putative druggable site in the fenestration. Flecainide binds in the fenestration of rat Na_V1.5 formed between DII and DIII of the pore.