Journal
FEBS JOURNAL
Volume 272, Issue 7, Pages 1639-1648Publisher
WILEY
DOI: 10.1111/j.1742-4658.2005.04583.x
Keywords
(S)-4-AHCP; bicyclical AMPA analogue; ionotropic glutamate receptor; ligand-binding core; X-ray crystallography
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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 K-i 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 degrees). 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.
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