GluR2 ligand‐binding core complexes: importance of the isoxazolol moiety and 5‐substituent for the binding mode of AMPA‐type agonists

FEBS Letters

Egebjerg, J¹  Kasper, C³  Lunn, M.-L³  Kastrup, J.S³  Gouaux, E²  Liljefors, T³ 

[1] Department of Molecular and Structural Biology, University of Aarhus, C.F. Møllers Allé 130, DK-8000 Aarhus, Denmark;Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Columbia University, 650 W. 168 Street, New York, NY 10032, USA;Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark

关键词: AMPA analogue;    X-ray crystallography;    Ionotropic glutamate receptor;    Ligand-binding core;    Agonist;    GluR;    glutamate receptor;    iGluR;    ionotropic glutamate receptor;    AMPA;    2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid;    NMDA;    N-methyl-D-aspartic acid;    Des-Me-AMPA;    2-amino-3-(3-hydroxy-4-isoxazolyl)propionic acid;    2-Me-Tet-AMPA;    2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)-4-isoxazolyl]propionic acid;   

DOI  :  10.1016/S0014-5793(02)03496-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

X-ray structures of the GluR2 ligand-binding core in complex with (S)-Des-Me-AMPA and in the presence and absence of zinc ions have been determined. (S)-Des-Me-AMPA, which is devoid of a substituent in the 5-position of the isoxazolol ring, only has limited interactions with the partly hydrophobic pocket of the ligand-binding site, and adopts an AMPA-like binding mode. The structures, in comparison with other agonist complex structures, disclose the relative importance of the isoxazolol ring and of the substituent in the 5-position for the mode of binding. A relationship appears to exist between the extent of interaction of the ligand with the hydrophobic pocket and the affinity of the ligand.

【 授权许可】

Unknown