PDBsum entry 2pbw

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protein ligands Protein-protein interface(s) links
Membrane protein PDB id
Protein chains
248 a.a. *
DOQ ×2
Waters ×317
* Residue conservation analysis
PDB id:
Name: Membrane protein
Title: Crystal structure of the ligand-binding core of iglur5 in co the partial agonist domoic acid at 2.5 a resolution
Structure: Glutamate receptor, ionotropic kainate 1. Chain: a, b. Synonym: glutamate receptor 5, glur-5, glur5. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: grik1, glur5. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.50Å     R-factor:   0.209     R-free:   0.248
Authors: H.Hald,P.Naur,M.Gajhede,J.S.Kastrup
Key ref:
H.Hald et al. (2007). Partial Agonism and Antagonism of the Ionotropic Glutamate Receptor iGLuR5: STRUCTURES OF THE LIGAND-BINDING CORE IN COMPLEX WITH DOMOIC ACID AND 2-AMINO-3-[5-tert-BUTYL-3-(PHOSPHONOMETHOXY)-4-ISOXAZOLYL]PROPIONIC ACID. J Biol Chem, 282, 25726-25736. PubMed id: 17581823 DOI: 10.1074/jbc.M700137200
29-Mar-07     Release date:   03-Jul-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P22756  (GRIK1_RAT) -  Glutamate receptor ionotropic, kainate 1
949 a.a.
248 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 
  Biological process     transport   1 term 
  Biochemical function     transporter activity     3 terms  


DOI no: 10.1074/jbc.M700137200 J Biol Chem 282:25726-25736 (2007)
PubMed id: 17581823  
H.Hald, P.Naur, D.S.Pickering, D.Sprogøe, U.Madsen, D.B.Timmermann, P.K.Ahring, T.Liljefors, A.Schousboe, J.Egebjerg, M.Gajhede, J.S.Kastrup.
More than 50 structures have been reported on the ligand-binding core of the ionotropic glutamate receptor iGluR2 that belongs to the 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid-type of receptors. In contrast, the ligand-binding core of the kainic acid-type receptor iGluR5 has only been crystallized with three different ligands. Hence, additional structures of iGluR5 are needed to broaden the understanding of the ligand-binding properties of iGluR5, and the conformational changes leading to channel opening and closing. Here, we present two structures of the ligand-binding core of iGluR5; one as a complex with the partial agonist (2S,3S,4S)-3-carboxymethyl-4-[(1Z,3E,5R)-5-carboxy-1-methyl-hexa-1,3-dienyl]-pyrrolidine-2-carboxylic acid (domoic acid) and one as a complex with the antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid ((S)-ATPO). In agreement with the partial agonist activity of domoic acid, the ligand-binding core of the iGluR5 complex is stabilized by domoic acid in a conformation that is 11 degrees more open than the conformation observed in the full agonist (S)-glutamic acid complex. This is primarily caused by the 5-carboxy-1-methyl-hexa-1,3-dienyl moiety of domoic acid and residues Val(685)-Thr(690) of iGluR5. An even larger domain opening of 28 degrees is introduced upon binding of the antagonist (S)-ATPO. It appears that the span of domain opening is much larger in the ligand-binding core of iGluR5 (30 degrees ) compared with what has been observed in iGluR2 (19 degrees ). Similarly, much larger variation in the distances between transmembrane linker residues in the two protomers comprising the dimer is observed in iGluR5 as compared with iGluR2.
  Selected figure(s)  
Figure 1.
FIGURE 1. Chemical structures of domoic acid, kainic acid, (S)-ATPO, UBP302, and UBP310. The atom numbering of domoic acid is shown in italics and is according to Nanao et al. (46) (PDB entry code 1YAE). The numbering of (S)-ATPO is according to Hogner et al. (14) (PDB entry code 1N0T). See abbreviations for compound names.
Figure 4.
FIGURE 4. Two-dimensional ligand-receptor interaction plots of iGluR5-S1S2 in complex with domoic acid (A) and (S)-ATPO (B). iGluR5-S1S2 polar residues are shown as purple circles, acidic residues as purple/red, basic residues as purple/blue, and hydrophobic residues in green. Contacts from ligand to receptor side chains as calculated by the program MOE are shown as green arrows and from ligand to receptor backbone as blue arrows. Water molecules in contact with ligands are shown as white circles and their contacts as yellow lines. The extent of ligand and receptor exposure is shown as blue spheres differing in size.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 25726-25736) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20558186 G.M.Alushin, D.Jane, and M.L.Mayer (2011).
Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive antagonists.
  Neuropharmacology, 60, 126-134.
PDB codes: 2qs1 2qs2 2qs4
21372852 M.L.Mayer (2011).
Glutamate receptor ion channels: where do all the calories go?
  Nat Struct Mol Biol, 18, 253-254.  
20163115 A.H.Ahmed, and R.E.Oswald (2010).
Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.
  J Med Chem, 53, 2197-2203.
PDB codes: 3lsf 3lsl 3lsw 3lsx
21116416 I.Nogueira, A.Lobo-da-Cunha, A.Afonso, S.Rivera, J.Azevedo, R.Monteiro, R.Cervantes, A.Gago-Martinez, and V.Vasconcelos (2010).
Toxic effects of domoic acid in the seabream Sparus aurata.
  Mar Drugs, 8, 2721-2732.  
19737573 P.A.Postila, G.T.Swanson, and O.T.Pentikäinen (2010).
Exploring kainate receptor pharmacology using molecular dynamics simulations.
  Neuropharmacology, 58, 515-527.  
19003990 A.H.Ahmed, Q.Wang, H.Sondermann, and R.E.Oswald (2009).
Structure of the S1S2 glutamate binding domain of GLuR3.
  Proteins, 75, 628-637.
PDB codes: 3dln 3dp4 3dp6
19116277 D.R.Artis, J.J.Lin, C.Zhang, W.Wang, U.Mehra, M.Perreault, D.Erbe, H.I.Krupka, B.P.England, J.Arnold, A.N.Plotnikov, A.Marimuthu, H.Nguyen, S.Will, M.Signaevsky, J.Kral, J.Cantwell, C.Settachatgull, D.S.Yan, D.Fong, A.Oh, S.Shi, P.Womack, B.Powell, G.Habets, B.L.West, K.Y.Zhang, M.V.Milburn, G.P.Vlasuk, K.P.Hirth, K.Nolop, G.Bollag, P.N.Ibrahim, and J.F.Tobin (2009).
Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent.
  Proc Natl Acad Sci U S A, 106, 262-267.
PDB codes: 3et0 3et1 3et2 3et3
18623169 L.Bunch, and P.Krogsgaard-Larsen (2009).
Subtype selective kainic acid receptor agonists: discovery and approaches to rational design.
  Med Res Rev, 29, 3.  
19544581 M.Du, A.Rambhadran, and V.Jayaraman (2009).
Vibrational spectroscopic investigation of the ligand binding domain of kainate receptors.
  Protein Sci, 18, 1585-1591.  
18658129 M.Du, A.Rambhadran, and V.Jayaraman (2008).
Luminescence resonance energy transfer investigation of conformational changes in the ligand binding domain of a kainate receptor.
  J Biol Chem, 283, 27074-27078.  
18728725 O.M.Pulido (2008).
Domoic acid toxicologic pathology: a review.
  Mar Drugs, 6, 180-219.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.