4IY5

Crystal structure of the glua2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and CX516 at 2.0 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.155 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain

Krintel, C.Harpsoe, K.Zachariassen, L.G.Peters, D.Frydenvang, K.Pickering, D.S.Gajhede, M.Kastrup, J.S.

(2013) Acta Crystallogr D Biol Crystallogr 69: 1645-1652

  • DOI: https://doi.org/10.1107/S0907444913011839
  • Primary Citation of Related Structures:  
    4IY5, 4IY6

  • PubMed Abstract: 

    Positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX614 have been shown to inhibit the deactivation of AMPA receptors with a less pronounced effect on desensitization. Despite CX516 being an extensively investigated AMPA receptor modulator and one of the few clinically evaluated compounds, the binding mode of CX516 to AMPA receptors has not been reported. Here, the structures of a GluA2 ligand-binding domain mutant in complex with CX516 and the 3-methylpiperidine analogue of CX516 (Me-CX516) are reported. The structures show that the binding modes of CX516 and Me-CX516 are similar to those of aniracetam and CX614 and that there is limited space for substitution at the piperidine ring of CX516. The results therefore support that CX516, like aniracetam and CX614, modulates deactivation of AMPA receptors.


  • Organizational Affiliation

    Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor 2
A, B
263Rattus norvegicusMutation(s): 2 
Gene Names: Glur2Gria2
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
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CX5
Query on CX5

Download Ideal Coordinates CCD File 
H [auth B]piperidin-1-yl(quinoxalin-6-yl)methanone
C14 H15 N3 O
ANDGGVOPIJEHOF-UHFFFAOYSA-N
GLU
Query on GLU

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
GLUTAMIC ACID
C5 H9 N O4
WHUUTDBJXJRKMK-VKHMYHEASA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
F [auth A],
J [auth B],
K [auth B],
N [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B],
M [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A],
O [auth B],
P [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.155 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.08α = 90
b = 121.69β = 90
c = 47.3γ = 90
Software Package:
Software NamePurpose
PHASERphasing
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-09
    Type: Initial release
  • Version 1.1: 2017-08-23
    Changes: Data collection, Refinement description, Source and taxonomy
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description