TY - JOUR
T1 - Model structures of the N-methyl-D-aspartate receptor subunit NR1 explain the molecular recognition of agonist and antagonist ligands
AU - Moretti, Loris
AU - Pentikäinen, Olli T.
AU - Settimo, Luca
AU - Johnson, Mark S.
PY - 2004/3
Y1 - 2004/3
N2 - Molecular models of the ligand-binding domain of N-methyl-D-aspartate subunit R1 (NR1) were made using the published crystal structures of rat glutamate receptor B (GluRB), the bacterial glutamate receptor (GluR0), and the glutamine-binding protein (QBP) of Escherichia coli. Separate models of NR1 were built to represent the ligand-binding conformation for agonist (glycine, D- and L-isomers of serine and alanine, and the partial agonist ligand D-cycloserine) and antagonist (5,7-dichloro-4-oxo-1,4-dihydroquinoline-2- carboxylic acid (DCKA) and E-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1-H- indole-2-carboxylic acid (MDL 105,519)) ligands. Side-chain conformations of residues within the NR1 ligand-binding site were selected that optimized the hydrophobic packing and hydrogen bonding among residues, while taking into account published data comparing receptor mutants with wild-type NR1. Ligands docked to the model structures provide a rational explanation for the observed differences in binding affinity and receptor activation among agonist and antagonist ligands. NR1 prefers smaller ligands (glycine, serine, and alanine) in comparison with GluRB and GluR0 that bind L-glutamate: the bulky side chain of W731 in NR1 dramatically reduces the size of the ligand-binding site, functioning to selectively restrict recognition to glycine and the D-isomers of serine and alanine. Nevertheless, many of the interactions seen for ligands bound to GluRB, GluR0, and periplasmic-binding proteins are present for the ligands docked to the model structures of NR1.
AB - Molecular models of the ligand-binding domain of N-methyl-D-aspartate subunit R1 (NR1) were made using the published crystal structures of rat glutamate receptor B (GluRB), the bacterial glutamate receptor (GluR0), and the glutamine-binding protein (QBP) of Escherichia coli. Separate models of NR1 were built to represent the ligand-binding conformation for agonist (glycine, D- and L-isomers of serine and alanine, and the partial agonist ligand D-cycloserine) and antagonist (5,7-dichloro-4-oxo-1,4-dihydroquinoline-2- carboxylic acid (DCKA) and E-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1-H- indole-2-carboxylic acid (MDL 105,519)) ligands. Side-chain conformations of residues within the NR1 ligand-binding site were selected that optimized the hydrophobic packing and hydrogen bonding among residues, while taking into account published data comparing receptor mutants with wild-type NR1. Ligands docked to the model structures provide a rational explanation for the observed differences in binding affinity and receptor activation among agonist and antagonist ligands. NR1 prefers smaller ligands (glycine, serine, and alanine) in comparison with GluRB and GluR0 that bind L-glutamate: the bulky side chain of W731 in NR1 dramatically reduces the size of the ligand-binding site, functioning to selectively restrict recognition to glycine and the D-isomers of serine and alanine. Nevertheless, many of the interactions seen for ligands bound to GluRB, GluR0, and periplasmic-binding proteins are present for the ligands docked to the model structures of NR1.
KW - Agonist binding
KW - Antagonist binding
KW - Ionotropic glutamate receptors
KW - Model structures
KW - NMDA receptor
KW - NR1 subunit
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U2 - 10.1016/j.jsb.2003.10.016
DO - 10.1016/j.jsb.2003.10.016
M3 - Article
C2 - 14960371
AN - SCOPUS:1042267373
VL - 145
SP - 205
EP - 215
JO - Journal of Structural Biology
JF - Journal of Structural Biology
SN - 1047-8477
IS - 3
ER -