3PD8

X-ray structure of the ligand-binding core of GluA2 in complex with (S)-7-HPCA at 2.5 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.180 

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Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid.

Frydenvang, K.Pickering, D.S.Greenwood, J.R.Krogsgaard-Larsen, N.Brehm, L.Nielsen, B.Vogensen, S.B.Hald, H.Kastrup, J.S.Krogsgaard-Larsen, P.Clausen, R.P.

(2010) J Med Chem 53: 8354-8361

  • DOI: https://doi.org/10.1021/jm101218a
  • Primary Citation of Related Structures:  
    3PD8, 3PD9

  • PubMed Abstract: 

    We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.


  • Organizational Affiliation

    Department of Medicinal Chemistry.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor 2
A, B, C
261Rattus norvegicusMutation(s): 0 
Gene Names: Glur2Gria2RAT
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
HA7
Query on HA7

Download Ideal Coordinates CCD File 
E [auth A],
J [auth B],
M [auth C]
(7S)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid
C7 H8 N2 O4
YRSIGIYXZNQZCI-BYPYZUCNSA-N
CAC
Query on CAC

Download Ideal Coordinates CCD File 
N [auth C]CACODYLATE ION
C2 H6 As O2
OGGXGZAMXPVRFZ-UHFFFAOYSA-M
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B],
I [auth B],
K [auth C],
L [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACY
Query on ACY

Download Ideal Coordinates CCD File 
G [auth A]ACETIC ACID
C2 H4 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HA7 PDBBind:  3PD8 Ki: 348 (nM) from 1 assay(s)
Binding MOAD:  3PD8 Ki: 108 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.618α = 90
b = 164.002β = 90
c = 47.62γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection
DENZOdata reduction
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-29
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-11-09
    Changes: Database references
  • Version 1.3: 2017-08-23
    Changes: Data collection, Source and taxonomy
  • Version 1.4: 2018-01-24
    Changes: Database references
  • Version 1.5: 2018-10-10
    Changes: Data collection, Database references, Structure summary
  • Version 1.6: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary