TY - JOUR T1 - Novel Mode of Antagonist Binding in NMDA Receptors Revealed by the Crystal Structure of the GluN1-GluN2A Ligand-Binding Domain Complexed to NVP-AAM077 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 22 LP - 29 DO - 10.1124/mol.116.107912 VL - 92 IS - 1 AU - Annabel Romero-Hernandez AU - Hiro Furukawa Y1 - 2017/07/01 UR - http://molpharm.aspetjournals.org/content/92/1/22.abstract N2 - 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. 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. ER -