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

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Bettina B Nielsen, Darryl S Pickering, Jeremy R Greenwood, Lotte Brehm, Michael Gajhede, Arne Schousboe, Jette S Kastrup

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.
Original languageEnglish
JournalFEBS Journal
Volume272
Issue number7
Pages (from-to)1639-48
Number of pages9
ISSN1742-464X
DOIs
Publication statusPublished - 2005

Bibliographical note

Keywords: Alanine; Animals; Cells, Cultured; Female; Isoxazoles; Ligands; Receptors, AMPA; Spodoptera; Xenopus laevis

ID: 20122569