AMPA RECEPTORS AND BACTERIAL PERIPLASMIC AMINO ACID-BINDING PROTEINS SHARE THE IONIC MECHANISM OF LIGAND RECOGNITION

In order to identify key structural determinants for ligand recognitio n, we subjected the ligand-binding domain of the alpha-amino-3-hydroxy -5-methyl-4-isoxazole propionic acid (AMPA)-selective glutamate recept or GluR-D subunit to site-directed mutagenesis. Based on the analysis of the [H-3]AMPA-binding properties of the mutated binding sites, we c onstructed a revised three-dimensional model of the ligand-binding sit e, different in many respects from previously published models. In par ticular, our results indicate that the residues Arg507 and Glu727 repr esent the structural and functional correlates of Arg77 and Asp161 in the homologous bacterial lysine/ornithine/arginine-binding protein and histidine-binding protein, and directly interact with the alpha-carbo xyl and alpha-amino group of the bound ligand, respectively. In contra st, Glu424, implicated previously in ionic interactions with the a-ami no group of the agonist, is unlikely to have such a role in ligand bin ding. Our results indicate that glutamate receptors share with the bac terial polar amino acid-binding proteins the fundamental mechanism of amino acid recognition.