title: Exploring the GluR2 ligand-binding core in complex with the bicyclical AMPA analogue (S)-4-AHCP.
abstract: 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.
authors.affiliation: Biostructural Research, Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
authors.forename: Bettina B
authors.initials: BB
authors.lastname: Nielsen
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Greenwood
authors.forename: Lotte
authors.initials: L
authors.lastname: Brehm
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007555:Isoxazoles / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D018091:Receptors, AMPA / Q000378:metabolism*; D018411:Spodoptera; D014982:Xenopus laevis
chemical_list: C473672:2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta(d)isoxazol-4-yl)propionic acid; D007555:Isoxazoles; D008024:Ligands; D018091:Receptors, AMPA; D000409:Alanine; C104722:glutamate receptor ionotropic, AMPA 2