PDBsum entry 2wky

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protein ligands metals Protein-protein interface(s) links
Membrane protein PDB id
Protein chains
255 a.a. *
IBC ×2
_CL ×2
Waters ×295
* Residue conservation analysis
PDB id:
Name: Membrane protein
Title: Crystal structure of the ligand-binding core of glur5 in complex with the agonist 4-ahcp
Structure: Glutamate receptor, ionotropic kainate 1. Chain: a, b. Fragment: ligand-binding core, residues 430-544,667-806. Synonym: glutamate receptor 5, glur-5, glur5. Engineered: yes
Source: Rattus norvegicus. Rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.20Å     R-factor:   0.211     R-free:   0.248
Authors: P.Naur,M.Gajhede,J.S.Kastrup
Key ref: R.P.Clausen et al. (2009). 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. J Med Chem, 52, 4911-4922. PubMed id: 19588945 DOI: 10.1021/jm900565c
18-Jun-09     Release date:   21-Jul-09    
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Protein chains
Pfam   ArchSchema ?
P22756  (GRIK1_RAT) -  Glutamate receptor ionotropic, kainate 1
949 a.a.
255 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biochemical function     ionotropic glutamate receptor activity     2 terms  


DOI no: 10.1021/jm900565c J Med Chem 52:4911-4922 (2009)
PubMed id: 19588945  
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.
R.P.Clausen, P.Naur, A.S.Kristensen, J.R.Greenwood, M.Strange, H.Bräuner-Osborne, A.A.Jensen, A.S.Nielsen, U.Geneser, L.M.Ringgaard, B.Nielsen, D.S.Pickering, L.Brehm, M.Gajhede, P.Krogsgaard-Larsen, J.S.Kastrup.
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.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21349697 M.L.Mayer (2011).
Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation.
  Curr Opin Neurobiol, 21, 283-290.  
20945316 R.Risgaard, K.B.Hansen, and R.P.Clausen (2010).
Partial agonists and subunit selectivity at NMDA receptors.
  Chemistry, 16, 13910-13918.  
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