Novel mode of antagonist binding in NMDA receptors revealed by the crystal structure of the GluN1-GluN2A ligand-binding domain complexed to NVP-AAM077

Romero-Hernandez, A., Furukawa, H. (2017) 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 (1). pp. 22-29. ISSN 0026-895x

URL: https://www.ncbi.nlm.nih.gov/pubmed/28468946
DOI: 10.1124/mol.116.107912

Abstract

Competitive antagonists against N-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. Here, we present the crystal structure of the isolated ligand-binding domain (LBD) 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.

Item Type: Paper
Uncontrolled Keywords: Func. analysis receptor/ion channel mutants Glutamate Mutagenesis/Chimeric approaches Structure determinations X-ray crystallography
Subjects: bioinformatics > genomics and proteomics > small molecules > NMDA receptor
structural biology
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Matt Covey
Date Deposited: 11 May 2017 15:04
Last Modified: 08 Sep 2017 14:38
PMCID: PMC5452055
Related URLs:
Dataset ID:
URI: http://repository.cshl.edu/id/eprint/34737

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