PDBsum entry 2f34

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protein ligands metals Protein-protein interface(s) links
Membrane protein PDB id
Protein chains
251 a.a. *
1PE ×2
UBA ×2
_CL ×2
Waters ×482
* Residue conservation analysis
PDB id:
Name: Membrane protein
Title: Crystal structure of the glur5 ligand binding core dimer wit at 1.74 angstroms resolution
Structure: Glutamate receptor, ionotropic kainate 1. Chain: a, b. Fragment: glur5 ligand binding core (sequence database 446- 682-821). Synonym: glutamate receptor 5, glur-5, glur5. Engineered: yes. Mutation: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: grik1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
1.74Å     R-factor:   0.183     R-free:   0.211
Authors: M.L.Mayer
Key ref: M.L.Mayer et al. (2006). Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci, 26, 2852-2861. PubMed id: 16540562 DOI: 10.1523/JNEUROSCI.0123-06.2005
18-Nov-05     Release date:   04-Apr-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P22756  (GRIK1_RAT) -  Glutamate receptor ionotropic, kainate 1
949 a.a.
251 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: 10.1523/JNEUROSCI.0123-06.2005 J Neurosci 26:2852-2861 (2006)
PubMed id: 16540562  
Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists.
M.L.Mayer, A.Ghosal, N.P.Dolman, D.E.Jane.
Glutamate receptor (GluR) ion channels mediate fast synaptic transmission in the mammalian CNS. Numerous crystallographic studies, the majority on the GluR2-subtype AMPA receptor, have revealed the structural basis for binding of subtype-specific agonists. In contrast, because there are far fewer antagonist-bound structures, the mechanisms for antagonist binding are much less well understood, particularly for kainate receptors that exist as multiple subtypes with a distinct biology encoded by the GluR5-7, KA1, and KA2 genes. We describe here high-resolution crystal structures for the GluR5 ligand-binding core complex with UBP302 and UBP310, novel GluR5-selective antagonists. The crystal structures reveal the structural basis for the high selectivity for GluR5 observed in radiolabel displacement assays for the isolated ligand binding cores of the GluR2, GluR5, and GluR6 subunits and during inhibition of glutamate-activated currents in studies on full-length ion channels. The antagonists bind via a novel mechanism and do not form direct contacts with the E723 side chain as occurs in all previously solved AMPA and kainate receptor agonist and antagonist complexes. This results from a hyperextension of the ligand binding core compared with previously solved structures. As a result, in dimer assemblies, there is a 22 A extension of the ion channel linkers in the transition from antagonist- to glutamate-bound forms. This large conformational change is substantially different from that described for AMPA receptors, was not possible to predict from previous work, and suggests that glutamate receptors are capable of much larger movements than previously thought.

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
  21522138 K.M.Vance, N.Simorowski, S.F.Traynelis, and H.Furukawa (2011).
Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors.
  Nat Commun, 2, 294.
PDB codes: 3oek 3oel 3oem 3oen
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
19962997 L.L.Lash-Van Wyhe, P.A.Postila, K.Tsubone, M.Sasaki, O.T.Pentikäinen, R.Sakai, and G.T.Swanson (2010).
Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine.
  Neuropharmacology, 58, 640-649.  
19737573 P.A.Postila, G.T.Swanson, and O.T.Pentikäinen (2010).
Exploring kainate receptor pharmacology using molecular dynamics simulations.
  Neuropharmacology, 58, 515-527.  
20856958 R.Vijayan, M.A.Sahai, T.Czajkowski, and P.C.Biggin (2010).
A comparative analysis of the role of water in the binding pockets of ionotropic glutamate receptors.
  Phys Chem Chem Phys, 12, 14057-14066.  
20404149 U.Das, J.Kumar, M.L.Mayer, and A.J.Plested (2010).
Domain organization and function in GluK2 subtype kainate receptors.
  Proc Natl Acad Sci U S A, 107, 8463-8468.  
19284741 A.H.Ahmed, M.D.Thompson, M.K.Fenwick, B.Romero, A.P.Loh, D.E.Jane, H.Sondermann, and R.E.Oswald (2009).
Mechanisms of antagonism of the GluR2 AMPA receptor: structure and dynamics of the complex of two willardiine antagonists with the glutamate binding domain.
  Biochemistry, 48, 3894-3903.
PDB codes: 3h03 3h06
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
18687343 A.J.Plested, and M.L.Mayer (2009).
Engineering a high-affinity allosteric binding site for divalent cations in kainate receptors.
  Neuropharmacology, 56, 114-120.  
19776277 A.J.Plested, and M.L.Mayer (2009).
AMPA receptor ligand binding domain mobility revealed by functional cross linking.
  J Neurosci, 29, 11912-11923.  
19297335 K.Frydenvang, L.L.Lash, P.Naur, P.A.Postila, D.S.Pickering, C.M.Smith, M.Gajhede, M.Sasaki, R.Sakai, O.T.Pentikaïnen, G.T.Swanson, and J.S.Kastrup (2009).
Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine.
  J Biol Chem, 284, 14219-14229.
PDB codes: 3gba 3gbb
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.  
19224535 M.Ouardouz, E.Coderre, A.Basak, A.Chen, G.W.Zamponi, S.Hameed, R.Rehak, X.Yin, B.D.Trapp, and P.K.Stys (2009).
Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors.
  Ann Neurol, 65, 151-159.  
19224531 M.Ouardouz, E.Coderre, G.W.Zamponi, S.Hameed, X.Yin, B.D.Trapp, and P.K.Stys (2009).
Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors.
  Ann Neurol, 65, 160-166.  
19135896 R.Benton, K.S.Vannice, C.Gomez-Diaz, and L.B.Vosshall (2009).
Variant ionotropic glutamate receptors as chemosensory receptors in Drosophila.
  Cell, 136, 149-162.  
18789344 S.L.Dargan, V.R.Clarke, G.M.Alushin, J.L.Sherwood, R.Nisticò, Z.A.Bortolotto, A.M.Ogden, D.Bleakman, A.J.Doherty, D.Lodge, M.L.Mayer, S.M.Fitzjohn, D.E.Jane, and G.L.Collingridge (2009).
ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function.
  Neuropharmacology, 56, 121-130.
PDB code: 2qs3
18549784 A.J.Plested, R.Vijayan, P.C.Biggin, and M.L.Mayer (2008).
Molecular basis of kainate receptor modulation by sodium.
  Neuron, 58, 720-735.
PDB codes: 3c31 3c32 3c33 3c34 3c35 3c36
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.  
18491377 T.Mamonova, K.Speranskiy, and M.Kurnikova (2008).
Interplay between structural rigidity and electrostatic interactions in the ligand binding domain of GluR2.
  Proteins, 73, 656-671.  
17359918 A.J.Plested, and M.L.Mayer (2007).
Structure and mechanism of kainate receptor modulation by anions.
  Neuron, 53, 829-841.
PDB code: 2ojt
17937910 A.Y.Lau, and B.Roux (2007).
The free energy landscapes governing conformational changes in a glutamate receptor ligand-binding domain.
  Structure, 15, 1203-1214.  
17199015 B.S.Meldrum, and M.A.Rogawski (2007).
Molecular targets for antiepileptic drug development.
  Neurotherapeutics, 4, 18-61.  
17521566 D.L.Minor (2007).
The neurobiologist's guide to structural biology: a primer on why macromolecular structure matters and how to evaluate structural data.
  Neuron, 54, 511-533.  
17578923 P.Gorostiza, M.Volgraf, R.Numano, S.Szobota, D.Trauner, and E.Y.Isacoff (2007).
Mechanisms of photoswitch conjugation and light activation of an ionotropic glutamate receptor.
  Proc Natl Acad Sci U S A, 104, 10865-10870.  
18073551 R.Dickinson, B.K.Peterson, P.Banks, C.Simillis, J.C.Martin, C.A.Valenzuela, M.Maze, and N.P.Franks (2007).
Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology.
  Anesthesiology, 107, 756-767.  
17178406 A.Priel, S.Selak, J.Lerma, and Y.Stern-Bach (2006).
Block of kainate receptor desensitization uncovers a key trafficking checkpoint.
  Neuron, 52, 1037-1046.  
17115050 M.C.Weston, P.Schuck, A.Ghosal, C.Rosenmund, and M.L.Mayer (2006).
Conformational restriction blocks glutamate receptor desensitization.
  Nat Struct Mol Biol, 13, 1120-1127.
PDB codes: 2i0b 2i0c
16554805 M.L.Mayer (2006).
Glutamate receptors at atomic resolution.
  Nature, 440, 456-462.  
16847640 P.Pinheiro, and C.Mulle (2006).
Kainate receptors.
  Cell Tissue Res, 326, 457-482.  
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.