Exploring the GluR2 ligand‐binding core in complex with the bicyclical AMPA analogue (S)‐4‐AHCP

The X-ray structure of the ionotropic GluR2 ligand-binding core (GluR2-S1S2J) in complex with the bicyclical AMPA analogue (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]-4-isoxazolyl)propionic acid [(S)-4-AHCP] has been determined, as well as the binding pharmacology of this construct and of the full-length GluR2 receptor. (S)-4-AHCP binds with a glutamate-like binding mode and the ligand adopts two different conformations. The Ki of (S)-4-AHCP at GluR2-S1S2J was determined to be 185 ± 29 nm and at full-length GluR2(R)o it was 175 ± 8 nm. (S)-4-AHCP appears to elicit partial agonism at GluR2 by inducing an intermediate degree of domain closure (17°). Also, functionally (S)-4-AHCP has an efficacy of 0.38 at GluR2(Q)i, relative to (S)-glutamate. The proximity of bound (S)-4-AHCP to domain D2 prevents full D1–D2 domain closure, which is limited by steric repulsion, especially between Leu704 and the ligand.