5FHM

Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with (S)-2-Amino-3-(5-(2-(3-(aminomethyl)benzyl)-2H-tetrazol-5-yl)-3-hydroxyisoxazol-4-yl)propanoic acid at resolution 1.55 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.137 
  • R-Value Observed: 0.138 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Tweaking Subtype Selectivity and Agonist Efficacy at (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) Receptors in a Small Series of BnTetAMPA Analogues.

Wang, S.Y.Larsen, Y.Navarrete, C.V.Jensen, A.A.Nielsen, B.Al-Musaed, A.Frydenvang, K.Kastrup, J.S.Pickering, D.S.Clausen, R.P.

(2016) J Med Chem 59: 2244-2254

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01982
  • Primary Citation of Related Structures:  
    5FHM, 5FHN, 5FHO

  • PubMed Abstract: 

    A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.


  • 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,Glutamate receptor 2
A, B
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 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5XP
Query on 5XP

Download Ideal Coordinates CCD File 
F [auth A](2~{S})-3-[5-[2-[[3-(aminomethyl)phenyl]methyl]-1,2,3,4-tetrazol-5-yl]-3-oxidanyl-1,2-oxazol-4-yl]-2-azanyl-propanoic acid
C15 H17 N7 O4
RVAKWTBISFVYTO-NSHDSACASA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
P [auth B]
Q [auth B]
C [auth A],
D [auth A],
E [auth A],
P [auth B],
Q [auth B],
R [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A],
S [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
I [auth A]
J [auth A]
K [auth A]
L [auth A]
M [auth A]
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
W [auth B],
X [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
H [auth A],
T [auth B],
U [auth B],
V [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
LI
Query on LI

Download Ideal Coordinates CCD File 
N [auth A],
O [auth B]
LITHIUM ION
Li
HBBGRARXTFLTSG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5XP BindingDB:  5FHM Ki: min: 1530, max: 8150 (nM) from 3 assay(s)
EC50: min: 4.97e+4, max: 4.32e+5 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.137 
  • R-Value Observed: 0.138 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.51α = 90
b = 94.056β = 90
c = 96.112γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-02
    Type: Initial release
  • Version 1.1: 2016-03-23
    Changes: Database references
  • Version 1.2: 2018-01-17
    Changes: Data collection
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description