tailieunhanh - Báo cáo khoa học: 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-hyd-roxy-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. | ềFEBS Journal Exploring the GluR2 ligand-binding core in complex with the bicyclical AMPA analogue S -4-AHCP Bettina B. Nielsen1 Darryl S. Pickering2 Jeremy R. Greenwood1 Lotte Brehm1 Michael Gajhede1 Arne Schousboe2 and Jette S. Kastrup1 1 BiostructuralResearch Department of MedicinalChemistry Danish University of PharmaceuticalSciences Copenhagen Denmark 2 Department of Pharmacology Danish University of PharmaceuticalSciences Copenhagen Denmark Keywords S -4-AHCP bicyclicalAMPA analogue ionotropic glutamate receptor ligand-binding core X-ray crystallography Correspondence J. S. Kastrup BiostructuralResearch Department of Medicinal Chemistry Danish University of Pharmaceutical Sciences Universitetsparken 2 DK-2100 Copenhagen Denmark Fax 45 3530 6040 Tel 45 3530 6486 E-mail jsk@ Received 28 September 2004 revised 18 January 2005 accepted 25 January 2005 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-hyd-roxy-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 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. doi The main excitatory amino acid in the central nervous system S -glutamate exerts its actions by binding to three different classes of ionotropic glutamate receptors iGluRs and three .