3TZA

Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with the antagonist (S)-2-amino-3-(2-(2-carboxyethyl)-5-chloro-4-nitrophenyl)propionic acid at 1.9A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

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This is version 1.3 of the entry. See complete history


Literature

A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: synthesis, resolution, pharmacology, and crystal structure

Szymanska, E.Frydenvang, K.Contreras-Sanz, A.Pickering, D.S.Frola, E.Serafimoska, Z.Nielsen, B.Kastrup, J.S.Johansen, T.N.

(2011) J Med Chem 54: 7289-7298

  • DOI: https://doi.org/10.1021/jm200862h
  • Primary Citation of Related Structures:  
    3TZA

  • PubMed Abstract: 

    In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o) and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8°. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor 2,Glutamate receptor 2
A, B
263Rattus norvegicusMutation(s): 0 
Gene Names: Gria2Glur2
UniProt
Find proteins for P19491 (Rattus norvegicus)
Explore P19491 
Go to UniProtKB:  P19491
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP19491
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
TZG BindingDB:  3TZA Ki: min: 3150, max: 2.27e+4 (nM) from 3 assay(s)
IC50: 3.00e+4 (nM) from 1 assay(s)
PDBBind:  3TZA Ki: 3150 (nM) from 1 assay(s)
Binding MOAD:  3TZA Ki: 3150 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.722α = 90
b = 61.835β = 94.09
c = 92.921γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-26
    Type: Initial release
  • Version 1.1: 2013-06-26
    Changes: Database references
  • Version 1.2: 2017-06-14
    Changes: Database references, Source and taxonomy, Structure summary
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description