Figure 6.

Cationic and sodium-bound electroneutral ligands in the channel. (A) The triethylammonium group of QX-314 is close to the Na_III site, the aromatic ring binds between F⁴ⁱ¹⁵ and Y⁴ⁱ²², and the ligand also interacts with Q^1p49 and F^3p49 in agreement with mutational data (Yamagishi et al., 2009). (B) The bulky moiety of quinidine fits the hotspot at the Na_III site, whereas the hydroxyl group donates an H bond to ^3p48O=C. (C and D) Two binding modes of cocaine. In one binding mode (C), the cocaine amino group binds at the Na_III site. In another binding mode (D), the amino group binds close to the putative Na_IV site and forms cation-π contacts with F⁴ⁱ¹⁵, whereas the opposite end of cocaine reaches I³ⁱ²³. (E and F) The long sipatrigine molecule can bind in the horizontal (E) and vertical (F) modes, forming many contacts with the channel. In the vertical mode, sipatrigine extends from the Na_III site to the hydrophobic region at levels i22-i23. (G and H) Side and extracellular views of lamotrigine. In the side view (G), repeat II is removed for clarity. In the extracellular view (H), lamotrigine and backbone carbonyls ^p48O=C are space filled. Lamotrigine binds to Na_III, which is coordinated by ^3p48O=C and ^4p48O=C, donates an H bond to ^2p48O=C, interacts with ^1p48O=C, π-stacks with F⁴ⁱ¹⁵, and approaches Y⁴ⁱ²². (I and J) Side and extracellular views at two similar binding modes of bisphenol A. Both aromatic rings are involved in π-cation interactions with Na_III, two hydroxyls donate H bonds to carbonyls ^p48O=C, and methyl groups bind between F⁴ⁱ¹⁵ and Y⁴ⁱ²². (K and L) Side views of lacosamide and phenytoin. Both ligands interact with Na_III and form H bonds with Q^1p49, whereas their aromatic rings bind between F⁴ⁱ¹⁵ and Y⁴ⁱ²².