Figure 4.

Hydrogen bonding interactions and binding modes of aniracetam and CX614. A, Top view of hydrogen bonding (dashed lines) between aniracetam, protein residues, and water molecules (blue spheres), in which the domains are color coded as shown in F. B, Side view of aniracetam hydrogen bonding interactions. C, View of hydrogen bonding interactions between CX614, protein, and water molecules from the top. D, CX614 interactions with protein and water molecules from the side. E, Binding of CX614 illustrated using CPK representation, showing residues Pro 494, Ser 497, and Ser 729 from each subunit, illustrating how the prolines form the “top” of the binding pocket and the serines form the base. F, A simple model to describe the mechanism of action of positive allosteric modulators such as aniracetam and CX614 on AMPA receptors. The diagram depicts a side view of the GluR2 ligand-binding core dimer in which domains 1 and 2 of protomer A are orange and blue, and domains 1 and 2 of protomer B are red and green, respectively. Agonists are represented by small blue spheres that bind between domains 1 and 2 and stabilize the closed-cleft conformation. Modulators, such as aniracetam and CX614 (yellow oval), bind on the backside of the ligand-binding core through interactions with a proline ceiling and a serine floor, at the interdomain hinge in the dimer interface, and stabilize the closed-cleft conformation of the ligand-binding core (dashed lines).