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 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.
Nielsen
Bettina B
BB
Biostructural Research, Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
Pickering
Darryl S
DS
Greenwood
Jeremy R
JR
Brehm
Lotte
L
Gajhede
Michael
M
Schousboe
Arne
A
Kastrup
Jette S
JS
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
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