RCSB PDB - 5EWM: CRYSTAL STRUCTURE OF AMINO TERMINAL DOMAINS OF THE NMDA RECEPTOR SUBUNIT GLUN1 AND GLUN2B IN COMPLEX WITH EVT-101

 5EWM

CRYSTAL STRUCTURE OF AMINO TERMINAL DOMAINS OF THE NMDA RECEPTOR SUBUNIT GLUN1 AND GLUN2B IN COMPLEX WITH EVT-101


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.76 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 5SMClick on this verticalbar to view detailsBest fitted NAGClick on this verticalbar to view details

This is version 2.2 of the entry. See complete history


Literature

A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists.

Stroebel, D.Buhl, D.L.Knafels, J.D.Chanda, P.K.Green, M.Sciabola, S.Mony, L.Paoletti, P.Pandit, J.

(2016) Mol Pharmacol 89: 541-551

  • DOI: https://doi.org/10.1124/mol.115.103036
  • Primary Citation of Related Structures:  
    5EWJ, 5EWL, 5EWM

  • PubMed Abstract: 

    N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathologic conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using X-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classic phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate that this novel binding site is physiologically relevant. Moreover, in silico docking unveils that GluN2B-selective antagonists broadly divide into two distinct classes according to binding pose. These data widen the allosteric and pharmacological landscape of NMDARs and offer a renewed structural framework for designing next-generation GluN2B antagonists with therapeutic value for brain disorders.


  • Organizational Affiliation

    Ecole Normale Supérieure, PSL Research University, CNRS, INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Paris, France (D.S., L.M., P.P.); Pfizer Worldwide Research and Development, Cambridge, Massachusetts (D.L.B., M.G., S.S.); and Pfizer Worldwide Research and Development, Groton, Connecticut (J.D.K., P.K.C., J.P.).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NMDA glutamate receptor subunit
A, C
390Xenopus laevisMutation(s): 2 
Gene Names: grin1NR1
UniProt
Find proteins for A0A1L8F5J9 (Xenopus laevis)
Explore A0A1L8F5J9 
Go to UniProtKB:  A0A1L8F5J9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A1L8F5J9
Glycosylation
Glycosylation Sites: 2
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor ionotropic, NMDA 2B
B, D
364Homo sapiensMutation(s): 1 
Gene Names: GRIN2BNMDAR2B
UniProt & NIH Common Fund Data Resources
Find proteins for Q13224 (Homo sapiens)
Explore Q13224 
Go to UniProtKB:  Q13224
PHAROS:  Q13224
GTEx:  ENSG00000273079 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13224
Glycosylation
Glycosylation Sites: 2Go to GlyGen: Q13224-1
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G22768VO
GlyCosmos:  G22768VO
GlyGen:  G22768VO
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5SM
Query on 5SM

Download Ideal Coordinates CCD File 
L [auth B],
R [auth D]
5-[3-[bis(fluoranyl)methyl]-4-fluoranyl-phenyl]-3-[(2-methylimidazol-1-yl)methyl]pyridazine
C16 H13 F3 N4
BOVUHBFXPNLTKF-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
G [auth A]
J [auth B]
K [auth B]
O [auth C]
P [auth D]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
F [auth A],
H [auth A],
I [auth A],
M [auth B],
N [auth C]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5SM BindingDB:  5EWM IC50: min: 12, max: 17 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.76 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 268.4α = 90
b = 60.61β = 116.27
c = 144.5γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
BUSTERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 5SMClick on this verticalbar to view detailsBest fitted NAGClick on this verticalbar to view details

Entry History 

Deposition Data

  • Released Date: 2016-03-02 
  • Deposition Author(s): Pandit, J.

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-02
    Type: Initial release
  • Version 1.1: 2016-03-09
    Changes: Database references
  • Version 1.2: 2016-04-13
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
  • Version 2.2: 2024-10-09
    Changes: Structure summary