Model structures of the N-methyl-D-aspartate receptor subunit NR1 explain the molecular recognition of agonist and antagonist ligands

Loris Moretti, Olli T. Pentikäinen, Luca Settimo, Mark S. Johnson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)205-215
Number of pages11
JournalJournal of Structural Biology
Volume145
Issue number3
DOIs
Publication statusPublished - Mar 2004

Keywords

  • Agonist binding
  • Antagonist binding
  • Ionotropic glutamate receptors
  • Model structures
  • NMDA receptor
  • NR1 subunit

ASJC Scopus subject areas

  • Structural Biology

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