Figure 8.

Comparison of the binding sites for aniracetam and CTZ. A, View down the twofold axis of the Ani/FW complex, showing aniracetam in red. Superimposed on the Ani/FW complex are the two CTZ molecules, taken from the GluR2 S1S2–CTZ cocrystal structure (Sun et al., 2002), after superposition of the protein structure on the Ani/FW protein structure. The molecular surfaces of the CTZ molecules are drawn as pink dots. B, View perpendicular to the molecular twofold axis. C, View perpendicular to the molecular twofold axis, as in B, relating drug-binding sites to their modes of action. Receptor activation increases the distance between domain II of each subunit (dark gray triangle). Subsequent to activation, channel desensitization occurs through rearrangements of domain I interactions (red triangle); this rearrangement is prevented when CTZ is bound. CX614 binds at the hinges between domains I and II (red circle). Rotating the view by 90° (D) allows a view of the CX614 interaction with the hinges, resulting in modulation of deactivation by stabilizing the closed-clamshell conformation.