1SYH

X-RAY STRUCTURE OF THE GLUR2 LIGAND-BINDING CORE (S1S2J) IN COMPLEX WITH (S)-CPW399 AT 1.85 A RESOLUTION.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.176 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Tyr702 Is an Important Determinant of Agonist Binding and Domain Closure of the Ligand-Binding Core of GluR2.

Frandsen, A.Pickering, D.S.Vestergaard, B.Kasper, C.Nielsen, B.B.Greenwood, J.R.Campiani, G.Fattorusso, C.Gajhede, M.Schousboe, A.Kastrup, J.S.

(2005) Mol Pharmacol 67: 703-713

  • DOI: https://doi.org/10.1124/mol.104.002931
  • Primary Citation of Related Structures:  
    1SYH, 1SYI, 1XHY

  • PubMed Abstract: 

    Ionotropic glutamate receptors mediate most rapid excitatory synaptic transmission in the mammalian central nervous system, and their involvement in neurological diseases has stimulated widespread interest in their structure and function. Despite a large number of agonists developed so far, few display selectivity among (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA)-receptor subtypes. The present study provides X-ray structures of the glutamate receptor 2 (GluR2)-selective partial agonist (S)-2-amino-3-(1,3,5,6,7-pentahydro-2,4-dioxocyclopenta[e] pyrimidin-1-yl) propanoic acid [(S)-CPW399] in complex with the ligand-binding core of GluR2 (GluR2-S1S2J) and with a (Y702F)GluR2-S1S2J mutant. In addition, the structure of the nonselective partial agonist kainate in complex with (Y702F)GluR2-S1S2J was determined. The results show that the selectivity of (S)-CPW399 toward full-length GluR2 relative to GluR3 is reflected in the binding data on the two soluble constructs, allowing the use of (Y702F)GluR2-S1S2J as a model system for studying GluR2/GluR3 selectivity. Structural comparisons suggest that selectivity arises from disruption of a water-mediated network between ligand and receptor. A D1-D2 domain closure occurs upon agonist binding. (S)-CPW399 and kainate induce greater domain closure in the Y702F mutant, indicating that these partial agonists here act in a manner more reminiscent of full agonists. Both kainate and (S)-CPW399 exhibited higher efficacy at (Y702F)GluR2(Q)i than at wild-type GluR2(Q)i. Whereas an excellent correlation exists between domain closure and efficacy of a range of agonists at full-length GluR2 determined by electrophysiology in Xenopus laevis oocytes, a direct correlation between agonist induced domain closure of (Y702F)GluR2-S1S2J and efficacy at the GluR3 receptor is not observed. Although it clearly controls selectivity, mutation of this residue alone is insufficient to explain agonist-induced conformational rearrangements occurring in this variant.


  • Organizational Affiliation

    Biostructural Research, Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor 2263Rattus 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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CPW
Query on CPW

Download Ideal Coordinates CCD File 
B [auth A](S)-2-AMINO-3-(1,3,5,7-PENTAHYDRO-2,4-DIOXO-CYCLOPENTA[E]PYRIMIDIN-1-YL) PROIONIC ACID
C10 H13 N3 O4
VSGUEKZRMJVQOH-LURJTMIESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CPW BindingDB:  1SYH Ki: min: 218, max: 2137 (nM) from 6 assay(s)
EC50: min: 1.39e+4, max: 2.24e+5 (nM) from 3 assay(s)
Binding MOAD:  1SYH Ki: 393 (nM) from 1 assay(s)
PDBBind:  1SYH Ki: 393 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.176 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.908α = 90
b = 96.353β = 90
c = 48.53γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2005-03-22
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description