title: Molecular mechanism of agonist recognition by the ligand-binding core of the ionotropic glutamate receptor 4.
abstract: The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) class of ionotropic glutamate receptors comprises four different subunits: iGluR1/iGluR2 and iGluR3/iGluR4 forming two subgroups. Three-dimensional structures have been reported only of the ligand-binding core of iGluR2. Here, we present two X-ray structures of a soluble construct of the R/G unedited flip splice variant of the ligand-binding core of iGluR4 (iGluR4(i)(R)-S1S2) in complex with glutamate or AMPA. Subtle, but important differences are found in the ligand-binding cavity between the two AMPA receptor subgroups at position 724 (Tyr in iGluR1/iGluR2 and Phe in iGluR3/iGluR4), which in iGluR4 may lead to displacement of a water molecule and hence points to the possibility to make subgroup specific ligands.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Kasper
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Peter
authors.initials: P
authors.lastname: Naur
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Jette Sandholm
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry*; D008024:Ligands; D011487:Protein Conformation; D018091:Receptors, AMPA / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000737:chemistry*
chemical_list: D008024:Ligands; D018091:Receptors, AMPA; C104724:glutamate receptor ionotropic, AMPA 4; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid