Mutational analysis of the glycine-binding site of the NMDA receptor: structural similarity with bacterial amino acid-binding proteins.
Activation of the NMDA subtype of ionotropic glutamate receptors requires binding of both L-glutamate and the coagonist glycine. Site-directed mutagenesis of the NMDAR1 (NR1) subunit revealed that aromatic residues at positions 390, 392, and 466 are crucial determinants of glycine binding. Glutamate efficacy was little affected by mutations at these positions; however, inhibition of channel gating by the glycine antagonist 7-chlorokynurenic acid was drastically reduced. In addition, glutamine (Q387), valine (V666), and serine (S669) substitutions were found to reduce glycine efficacy. Since the mutated residues correspond to positions forming the binding site of homologous bacterial amino acid-binding proteins, a common amino acid-binding fold appears to be conserved from prokaryotic periplasmic proteins to glutamate receptors in the mammalian brain.
Kuryatov
A
A
Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, Frankfurt, Federal Republic of Germany.
Laube
B
B
Betz
H
H
Kuhse
J
J
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005998:Glycine / Q000378:metabolism*; D007700:Kinetics; D046911:Macromolecular Substances; D008961:Models, Structural; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000502:physiology; D011487:Protein Conformation; D051381:Rats; D018009:Receptors, Glycine / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
D000596:Amino Acids; D002352:Carrier Proteins; D046911:Macromolecular Substances; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D005998:Glycine