4G8N

Crystal structure of the kainate receptor GluK3 ligand-binding domain in complex with the agonist G8M


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Pharmacological and structural characterization of conformationally restricted (S)-glutamate analogues at ionotropic glutamate receptors.

Juknaite, L.Venskutonyte, R.Assaf, Z.Faure, S.Gefflaut, T.Aitken, D.J.Nielsen, B.Gajhede, M.Kastrup, J.S.Bunch, L.Frydenvang, K.Pickering, D.S.

(2012) J Struct Biol 180: 39-46

  • DOI: https://doi.org/10.1016/j.jsb.2012.07.001
  • Primary Citation of Related Structures:  
    4G8M, 4G8N

  • PubMed Abstract: 

    Conformationally restricted glutamate analogues have been pharmacologically characterized at AMPA and kainate receptors and the crystal structures have been solved of the ligand (2S,1'R,2'S)-2-(2'-carboxycyclobutyl)glycine (CBG-IV) in complex with the ligand binding domains of the AMPA receptor GluA2 and the kainate receptor GluK3. These structures show that CBG-IV interacts with the binding pocket in the same way as (S)-glutamate. The binding affinities reveal that CBG-IV has high affinity at the AMPA and kainate receptor subtypes. Appreciable binding affinity of CBG-IV was not observed at NMDA receptors, where the introduction of the carbocyclic ring is expected to lead to a steric clash with binding site residues. CBG-IV was demonstrated to be an agonist at both GluA2 and the kainate receptor GluK1. CBG-IV showed high affinity binding to GluK1 compared to GluA2, GluK2 and GluK3, which exhibited lower affinity for CBG-IV. The structure of GluA2 LBD and GluK3 LBD in complex with CBG-IV revealed similar binding site interactions to those of (S)-glutamate. No major conformational rearrangements compared to the (S)-glutamate bound conformation were found in GluK3 in order to accommodate CBG-IV, in contrast with GluA2 where a shift in lobe D2 binding site residues occurs, leading to an increased binding cavity volume compared to the (S)-glutamate bound structure.


  • Organizational Affiliation

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


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor, ionotropic kainate 3258Rattus norvegicusMutation(s): 0 
Gene Names: GRIK3
UniProt
Find proteins for P42264 (Rattus norvegicus)
Explore P42264 
Go to UniProtKB:  P42264
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42264
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
G8M PDBBind:  4G8N Kd: 63 (nM) from 1 assay(s)
Binding MOAD:  4G8N Kd: 63 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 
  • Space Group: P 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.821α = 90
b = 67.821β = 90
c = 122.881γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata 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: 2012-08-29
    Type: Initial release
  • Version 1.1: 2012-11-14
    Changes: Database references
  • Version 1.2: 2017-08-23
    Changes: Data collection, Refinement description, Source and taxonomy
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description