2WKY

Crystal structure of the ligand-binding core of GluR5 in complex with the agonist 4-AHCP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.211 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

The Glutamate Receptor Glur5 Agonist (S)-2-Amino-3-(3-Hydroxy-7,8-Dihydro-6H-Cyclohepta[D]Isoxazol-4-Yl)Propionic Acid and the 8-Methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization

Clausen, R.P.Naur, P.Kristensen, A.S.Greenwood, J.R.Strange, M.Brauner-Osborne, H.Jensen, A.A.Nielsen, A.S.Geneser, U.Ringgaard, L.M.Nielsen, B.Pickering, D.S.Brehm, L.Gajhede, M.Krogsgaard-Larsen, P.Kastrup, J.S.

(2009) J Med Chem 52: 4911

  • DOI: https://doi.org/10.1021/jm900565c
  • Primary Citation of Related Structures:  
    2WKY

  • PubMed Abstract: 

    The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. rac@farma.ku.dk


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GLUTAMATE RECEPTOR, IONOTROPIC KAINATE 1
A, B
258Rattus norvegicusMutation(s): 0 
UniProt
Find proteins for P22756 (Rattus norvegicus)
Explore P22756 
Go to UniProtKB:  P22756
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22756
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
IBC Binding MOAD:  2WKY Ki: 2.57 (nM) from 1 assay(s)
PDBBind:  2WKY Ki: 2.57 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.211 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.31α = 90
b = 71.31β = 90
c = 234.958γ = 90
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-21
    Type: Initial release
  • Version 1.1: 2011-06-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-08-09
    Changes: Data collection
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description