5U8C

CRYSTAL STRUCTURE OF GLUN1/GLUN2A LIGAND-BINDING DOMAIN IN COMPLEX WITH GLYCINE AND NVP-AAM077

Summary for 5U8C

• Entry DOI: 10.2210/pdb5u8c/pdb
• Descriptor: Glutamate receptor ionotropic, NMDA 1, GLUTAMATE RECEPTOR IONOTROPIC, NMDA 2A, GLYCINE, ... (6 entities in total)
• Functional Keywords: receptor, glycine and nvp-aam077, transport protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 65746.70

Authors

Romero-Hernandez, A.,Furukawa, H. (deposition date: 2016-12-14, release date: 2017-05-17, Last modification date: 2024-10-30)

Primary citation

Romero-Hernandez, A.,Furukawa, H.
Novel Mode of Antagonist Binding in NMDA Receptors Revealed by the Crystal Structure of the GluN1-GluN2A Ligand-Binding Domain Complexed to NVP-AAM077.
Mol. Pharmacol., 92:22-29, 2017

PubMed Abstract: Competitive antagonists against -methyl-D-aspartate (NMDA) receptors have played critical roles throughout the history of neuropharmacology and basic neuroscience. There are currently numerous NMDA receptor antagonists containing a variety of chemical groups. Among those compounds, a GluN2-specific antagonist, (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic acid (NVP-AAM077), contains a unique combination of a dioxoquinoxalinyl ring, a bromophenyl group, and a phosphono group. In this study, we present the crystal structure of the isolated ligand-binding domain of the GluN1-GluN2A NMDA receptor in complex with the GluN1 agonist glycine and the GluN2A antagonist NVP-AAM077. The structure shows placement of the dioxoquinoxalinyl ring and the phosphono group of NVP-AAM077 in the glutamate-binding pocket in GluN2A and the novel interaction between the bromophenyl group and GluN1-Glu781 at the GluN1-GluN2A subunit interface. Site-directed mutagenesis of GluN1-Glu781 reduced the potency of inhibition by NVP-AAM077, thus confirming the involvement of the GluN1 subunit for binding of NVP-AAM077. The unique antagonist-binding pattern shown in this study provides a novel dimension to design and create antagonists with potential therapeutic values.

PubMed: 28468946
DOI: 10.1124/mol.116.107912

Experimental method

X-RAY DIFFRACTION (1.598 Å)