5NIH

Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with agonist LM-12b at 1.3 A resolution.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.158 
  • R-Value Work: 0.127 
  • R-Value Observed: 0.128 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors.

Mllerud, S.Pinto, A.Marconi, L.Frydenvang, K.Thorsen, T.S.Laulumaa, S.Venskutonyte, R.Winther, S.Moral, A.M.C.Tamborini, L.Conti, P.Pickering, D.S.Kastrup, J.S.

(2017) ACS Chem Neurosci 8: 2056-2064

  • DOI: https://doi.org/10.1021/acschemneuro.7b00201
  • Primary Citation of Related Structures:  
    5NEB, 5NF5, 5NF6, 5NG9, 5NIH, 5O4F

  • PubMed Abstract: 

    Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with K i of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (K i of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor 2A [auth B],
B [auth A]
264Rattus 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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8VE
Query on 8VE

Download Ideal Coordinates CCD File 
E [auth B],
K [auth A]
(3~{a}~{R},4~{S},6~{a}~{R})-1-methyl-4,5,6,6~{a}-tetrahydro-3~{a}~{H}-pyrrolo[3,4-c]pyrazole-3,4-dicarboxylic acid
C8 H11 N3 O4
MUCHMWUQFYVYSF-YUPRTTJUSA-N
SO4
Query on SO4

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

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

Download Ideal Coordinates CCD File 
O [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth B],
P [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
8VE Binding MOAD:  5NIH Ki: 134 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.158 
  • R-Value Work: 0.127 
  • R-Value Observed: 0.128 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.577α = 90
b = 87.954β = 90
c = 96.535γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
SCALAdata scaling
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: 2017-07-26
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Database references
  • Version 1.2: 2018-03-07
    Changes: Source and taxonomy
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description