5U8C

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

  • Classification: TRANSPORT PROTEIN
  • Organism(s): Rattus norvegicus
  • Expression System: Escherichia coli
  • Mutation(s): No 

  • Deposited: 2016-12-14 Released: 2017-05-17 
  • Deposition Author(s): Romero-Hernandez, A., Furukawa, H.
  • Funding Organization(s): National Institutes of Health/National Institute of Mental Health (NIH/NIMH), National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

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) Mol Pharmacol 92: 22-29

  • DOI: https://doi.org/10.1124/mol.116.107912
  • Primary Citation of Related Structures:  
    5U8C

  • PubMed 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.


  • Organizational Affiliation

    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.).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor ionotropic, NMDA 1292Rattus norvegicusMutation(s): 0 
Gene Names: Grin1Nmdar1
UniProt
Find proteins for P35439 (Rattus norvegicus)
Explore P35439 
Go to UniProtKB:  P35439
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35439
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GLUTAMATE RECEPTOR IONOTROPIC, NMDA 2A283Rattus norvegicusMutation(s): 0 
UniProt
Find proteins for Q00959 (Rattus norvegicus)
Explore Q00959 
Go to UniProtKB:  Q00959
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00959
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
84J
Query on 84J

Download Ideal Coordinates CCD File 
E [auth B][(R)-{[(1S)-1-(4-bromophenyl)ethyl]amino}(2,3-dihydroxyquinoxalin-5-yl)methyl]phosphonic acid
C17 H17 Br N3 O5 P
XXZGNAZRWCBSBK-HUTHGQBESA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
GLY
Query on GLY

Download Ideal Coordinates CCD File 
C [auth A]GLYCINE
C2 H5 N O2
DHMQDGOQFOQNFH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
84J Binding MOAD:  5U8C Ki: 29.58 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.55α = 90
b = 84.227β = 90
c = 121.218γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)United StatesMH085926
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM105730

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-17
    Type: Initial release
  • Version 1.1: 2017-06-07
    Changes: Database references, Other
  • Version 1.2: 2017-09-27
    Changes: Author supporting evidence
  • Version 1.3: 2019-11-27
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Refinement description