5DEX

Crystal structure of GluN1/GluN2A NMDA receptor agonist binding domains with glycine and antagonist, phenyl-ACEPC


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.213 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits.

Lind, G.E.Mou, T.C.Tamborini, L.Pomper, M.G.De Micheli, C.Conti, P.Pinto, A.Hansen, K.B.

(2017) Proc Natl Acad Sci U S A 

  • DOI: https://doi.org/10.1073/pnas.1707752114
  • Primary Citation of Related Structures:  
    5DEX, 5VIH, 5VII, 5VIJ

  • PubMed Abstract: 

    NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A-D). We describe highly potent ( S )-5-[( R )-2-amino-2-carboxyethyl]-4,5-dihydro-1 H -pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.


  • Organizational Affiliation

    Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812.


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
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  • 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 
Gene Names: Grin2a
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5E0
Query on 5E0

Download Ideal Coordinates CCD File 
D [auth B]5-[(2R)-2-amino-2-carboxyethyl]-1-phenyl-1H-pyrazole-3-carboxylic acid
C13 H13 N3 O4
MAXWODHGWOEWBN-SNVBAGLBSA-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
5E0 Binding MOAD:  5DEX Ki: 22.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.213 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.629α = 90
b = 87.302β = 90
c = 122.572γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

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 General Medical Sciences (NIH/NIGMS)United StatesP20GM103546

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-14
    Type: Initial release
  • Version 1.1: 2017-08-02
    Changes: Database references, Derived calculations
  • Version 1.2: 2017-08-23
    Changes: Author supporting evidence, Database references
  • Version 1.3: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description