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Molecular Pharmacology

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Research ArticleMini Special Section—Structural Basis of Receptor-Ligand Interactions

Novel Mode of Antagonist Binding in NMDA Receptors Revealed by the Crystal Structure of the GluN1-GluN2A Ligand-Binding Domain Complexed to NVP-AAM077

Annabel Romero-Hernandez and Hiro Furukawa
Molecular Pharmacology July 2017, 92 (1) 22-29; DOI: https://doi.org/10.1124/mol.116.107912
Annabel Romero-Hernandez
Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (A.R.-H., H.F.); and Watson School of Biological Sciences, Cold Spring Harbor, New York (A.R.-H., H.F.)
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Hiro Furukawa
Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (A.R.-H., H.F.); and Watson School of Biological Sciences, Cold Spring Harbor, New York (A.R.-H., H.F.)
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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. 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.

Footnotes

    • Received December 15, 2016.
    • Accepted May 1, 2017.
  • This work was supported by the National Institutes of Health [Grants MH085926 and GM105730], the Stanley Institute of Cognitive Genomics, and the Robertson Research Fund of Cold Spring Harbor Laboratory (to H.F.). A.R.-H. was funded by the Genentech Foundation Fellowship and the Starr Foundation.

  • https://doi.org/10.1124/mol.116.107912.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 92 (1)
Molecular Pharmacology
Vol. 92, Issue 1
1 Jul 2017
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Research ArticleMini Special Section—Structural Basis of Receptor-Ligand Interactions

Crystal Structure of NMDA Receptor Bound to NVP-AAM077

Annabel Romero-Hernandez and Hiro Furukawa
Molecular Pharmacology July 1, 2017, 92 (1) 22-29; DOI: https://doi.org/10.1124/mol.116.107912

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Research ArticleMini Special Section—Structural Basis of Receptor-Ligand Interactions

Crystal Structure of NMDA Receptor Bound to NVP-AAM077

Annabel Romero-Hernandez and Hiro Furukawa
Molecular Pharmacology July 1, 2017, 92 (1) 22-29; DOI: https://doi.org/10.1124/mol.116.107912
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