title: GluR2 ligand-binding core complexes: importance of the isoxazolol moiety and 5-substituent for the binding mode of AMPA-type agonists.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Kasper
authors.forename: M-L
authors.initials: ML
authors.lastname: Lunn
authors.forename: T
authors.initials: T
authors.lastname: Liljefors
authors.forename: E
authors.initials: E
authors.lastname: Gouaux
authors.forename: J
authors.initials: J
authors.lastname: Egebjerg
authors.forename: J S
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007555:Isoxazoles / Q000737:chemistry*; D008024:Ligands; D046911:Macromolecular Substances; D008715:Methionine / Q000737:chemistry; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D018091:Receptors, AMPA / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism; D013431:Sulfates / Q000737:chemistry; D015032:Zinc / Q000737:chemistry; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C468913:2-amino-3-(3-hydroxy-4-isoxazoyl)propionic acid; D007555:Isoxazoles; D008024:Ligands; D046911:Macromolecular Substances; D010455:Peptides; D018091:Receptors, AMPA; D013431:Sulfates; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D008715:Methionine; D015032:Zinc; C104722:glutamate receptor ionotropic, AMPA 2