PDBsum entry 1s50

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Membrane protein PDB id
Protein chain
258 a.a. *
Waters ×359
* Residue conservation analysis
PDB id:
Name: Membrane protein
Title: X-ray structure of the glur6 ligand binding core (s1s2a) in complex with glutamate at 1.65 a resolution
Structure: Glutamate receptor 6. Chain: a. Fragment: glur6 ligand binding core. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: glur6 residues 398-513 and 636-775. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.65Å     R-factor:   0.200     R-free:   0.230
Authors: M.L.Mayer
Key ref:
M.L.Mayer (2005). Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity. Neuron, 45, 539-552. PubMed id: 15721240 DOI: 10.1016/j.neuron.2005.01.031
19-Jan-04     Release date:   08-Feb-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P42260  (GRIK2_RAT) -  Glutamate receptor ionotropic, kainate 2
908 a.a.
258 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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: 10.1016/j.neuron.2005.01.031 Neuron 45:539-552 (2005)
PubMed id: 15721240  
Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity.
Little is known about the molecular mechanisms underlying differences in the ligand binding properties of AMPA, kainate, and NMDA subtype glutamate receptors. Crystal structures of the GluR5 and GluR6 kainate receptor ligand binding cores in complexes with glutamate, 2S,4R-4-methylglutamate, kainate, and quisqualate have now been solved. The structures reveal that the ligand binding cavities are 40% (GluR5) and 16% (GluR6) larger than for GluR2. The binding of AMPA- and GluR5-selective agonists to GluR6 is prevented by steric occlusion, which also interferes with the high-affinity binding of 2S,4R-4-methylglutamate to AMPA receptors. Strikingly, the extent of domain closure produced by the GluR6 partial agonist kainate is only 3 degrees less than for glutamate and 11 degrees greater than for the GluR2 kainate complex. This, together with extensive interdomain contacts between domains 1 and 2 of GluR5 and GluR6, absent from AMPA receptors, likely contributes to the high stability of GluR5 and GluR6 kainate complexes.
  Selected figure(s)  
Figure 4.
Figure 4. Docking GluR5-Selective Ligands in the GluR6 and GluR5 Ligand Binding Sites
Figure 7.
Figure 7. Interdomain Contacts in GluR5 and GluR2
  The above figures are reprinted by permission from Cell Press: Neuron (2005, 45, 539-552) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20621105 D.Stroebel, S.Carvalho, and P.Paoletti (2011).
Functional evidence for a twisted conformation of the NMDA receptor GluN2A subunit N-terminal domain.
  Neuropharmacology, 60, 151-158.  
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
21268287 J.L.Rasmussen, M.Storgaard, D.S.Pickering, and L.Bunch (2011).
Rational Design, Synthesis and Pharmacological Evaluation of the (2R)- and (2S)-Stereoisomers of 3-(2-Carboxypyrrolidinyl)-2-methyl Acetic Acid as Ligands for the Ionotropic Glutamate Receptors.
  ChemMedChem, 6, 498-504.  
21372852 M.L.Mayer (2011).
Glutamate receptor ion channels: where do all the calories go?
  Nat Struct Mol Biol, 18, 253-254.  
20199107 A.H.Ahmed, C.P.Ptak, and R.E.Oswald (2010).
Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA.
  Biochemistry, 49, 2843-2850.
PDB codes: 3m3f 3m3k 3m3l
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
20850188 D.Perrais, J.Veran, and C.Mulle (2010).
Gating and permeation of kainate receptors: differences unveiled.
  Trends Pharmacol Sci, 31, 516-522.  
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.  
21080238 T.Nakagawa (2010).
The biochemistry, ultrastructure, and subunit assembly mechanism of AMPA receptors.
  Mol Neurobiol, 42, 161-184.  
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.  
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
19946266 A.I.Sobolevsky, M.P.Rosconi, and E.Gouaux (2009).
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
  Nature, 462, 745-756.
PDB codes: 3kg2 3kgc
19617541 C.Chaudhry, A.J.Plested, P.Schuck, and M.L.Mayer (2009).
Energetics of glutamate receptor ligand binding domain dimer assembly are modulated by allosteric ions.
  Proc Natl Acad Sci U S A, 106, 12329-12334.  
19339989 C.Chaudhry, M.C.Weston, P.Schuck, C.Rosenmund, and M.L.Mayer (2009).
Stability of ligand-binding domain dimer assembly controls kainate receptor desensitization.
  EMBO J, 28, 1518-1530.
PDB codes: 3g3f 3g3g 3g3h 3g3i 3g3j 3g3k
19910922 E.Karakas, N.Simorowski, and H.Furukawa (2009).
Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit.
  EMBO J, 28, 3910-3920.
PDB codes: 3jpw 3jpy
  19184587 G.T.Swanson, and R.Sakai (2009).
Ligands for ionotropic glutamate receptors.
  Prog Mol Subcell Biol, 46, 123-157.  
19465914 J.Kumar, P.Schuck, R.Jin, and M.L.Mayer (2009).
The N-terminal domain of GluR6-subtype glutamate receptor ion channels.
  Nat Struct Mol Biol, 16, 631-638.
PDB codes: 3h6g 3h6h
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
19205024 K.Speranskiy, and M.G.Kurnikova (2009).
Modeling of peptides connecting the ligand-binding and transmembrane domains in the GluR2 glutamate receptor.
  Proteins, 76, 271-280.  
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.  
19342380 M.B.Gill, P.Vivithanaporn, and G.T.Swanson (2009).
Glutamate Binding and Conformational Flexibility of Ligand-binding Domains Are Critical Early Determinants of Efficient Kainate Receptor Biogenesis.
  J Biol Chem, 284, 14503-14512.  
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.  
19561126 N.Nayeem, Y.Zhang, D.K.Schweppe, D.R.Madden, and T.Green (2009).
A nondesensitizing kainate receptor point mutant.
  Mol Pharmacol, 76, 534-542.  
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.  
19342491 R.Numano, S.Szobota, A.Y.Lau, P.Gorostiza, M.Volgraf, B.Roux, D.Trauner, and E.Y.Isacoff (2009).
Nanosculpting reversed wavelength sensitivity into a photoswitchable iGluR.
  Proc Natl Acad Sci U S A, 106, 6814-6819.  
  20054492 S.B.Lee, C.H.Lee, S.N.Kim, K.M.Chung, Y.K.Cho, and K.N.Kim (2009).
Type II and III Taste Bud Cells Preferentially Expressed Kainate Glutamate Receptors in Rats.
  Korean J Physiol Pharmacol, 13, 455-460.  
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
19217376 W.Zhang, F.St-Gelais, C.P.Grabner, J.C.Trinidad, A.Sumioka, M.Morimoto-Tomita, K.S.Kim, C.Straub, A.L.Burlingame, J.R.Howe, and S.Tomita (2009).
A transmembrane accessory subunit that modulates kainate-type glutamate receptors.
  Neuron, 61, 385-396.  
19102704 A.Gill, A.Birdsey-Benson, B.L.Jones, L.P.Henderson, and D.R.Madden (2008).
Correlating AMPA receptor activation and cleft closure across subunits: crystal structures of the GluR4 ligand-binding domain in complex with full and partial agonists.
  Biochemistry, 47, 13831-13841.
PDB codes: 3en3 3epe
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
18710418 C.Villmann, J.Hoffmann, M.Werner, S.Kott, N.Strutz-Seebohm, T.Nilsson, and M.Hollmann (2008).
Different structural requirements for functional ion pore transplantation suggest different gating mechanisms of NMDA and kainate receptors.
  J Neurochem, 107, 453-465.  
18214958 E.J.Bjerrum, and P.C.Biggin (2008).
Rigid body essential X-ray crystallography: distinguishing the bend and twist of glutamate receptor ligand binding domains.
  Proteins, 72, 434-446.  
18032572 L.L.Lash, J.M.Sanders, N.Akiyama, M.Shoji, P.Postila, O.T.Pentikäinen, M.Sasaki, R.Sakai, and G.T.Swanson (2008).
Novel analogs and stereoisomers of the marine toxin neodysiherbaine with specificity for kainate receptors.
  J Pharmacol Exp Ther, 324, 484-496.  
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.  
18450751 M.L.Blanke, and A.M.VanDongen (2008).
Constitutive activation of the N-methyl-D-aspartate receptor via cleft-spanning disulfide bonds.
  J Biol Chem, 283, 21519-21529.  
18521762 S.M.Schmid, and M.Hollmann (2008).
To gate or not to gate: are the delta subunits in the glutamate receptor family functional ion channels?
  Mol Neurobiol, 37, 126-141.  
  18562501 T.J.Wilding, E.Fulling, Y.Zhou, and J.E.Huettner (2008).
Amino acid substitutions in the pore helix of GluR6 control inhibition by membrane fatty acids.
  J Gen Physiol, 132, 85-99.  
18823129 T.Mamonova, M.J.Yonkunas, and M.G.Kurnikova (2008).
Energetics of the cleft closing transition and the role of electrostatic interactions in conformational rearrangements of the glutamate receptor ligand binding domain.
  Biochemistry, 47, 11077-11085.  
19014388 X.Han, H.Tomitori, S.Mizuno, K.Higashi, C.Füll, T.Fukiwake, Y.Terui, P.Leewanich, K.Nishimura, T.Toida, K.Williams, K.Kashiwagi, and K.Igarashi (2008).
Binding of spermine and ifenprodil to a purified, soluble regulatory domain of the N-methyl-D-aspartate receptor.
  J Neurochem, 107, 1566-1577.  
18636091 Y.Yao, C.B.Harrison, P.L.Freddolino, K.Schulten, and M.L.Mayer (2008).
Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors.
  EMBO J, 27, 2158-2170.
PDB codes: 2rc7 2rc8 2rc9 2rca 2rcb
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
17379418 B.G.Kornreich, L.Niu, M.S.Roberson, and R.E.Oswald (2007).
Identification of C-terminal domain residues involved in protein kinase A-mediated potentiation of kainate receptor subtype 6.
  Neuroscience, 146, 1158-1168.  
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.  
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, and J.S.Kastrup (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.
PDB codes: 1vso 2pbw
17629578 I.H.Greger, E.B.Ziff, and A.C.Penn (2007).
Molecular determinants of AMPA receptor subunit assembly.
  Trends Neurosci, 30, 407-416.  
17880858 J.M.Amiel, and S.J.Mathew (2007).
Glutamate and anxiety disorders.
  Curr Psychiatry Rep, 9, 278-283.  
17934637 K.A.Mankiewicz, and V.Jayaraman (2007).
Glutamate receptors as seen by light: spectroscopic studies of structure-function relationships.
  Braz J Med Biol Res, 40, 1419-1427.  
17105731 W.Maier, R.Schemm, C.Grewer, and B.Laube (2007).
Disruption of interdomain interactions in the glutamate binding pocket affects differentially agonist affinity and efficacy of N-methyl-D-aspartate receptor activation.
  J Biol Chem, 282, 1863-1872.  
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.  
16406088 A.S.Kristensen, M.T.Geballe, J.P.Snyder, and S.F.Traynelis (2006).
Glutamate receptors: variation in structure-function coupling.
  Trends Pharmacol Sci, 27, 65-69.  
16709630 D.J.Wyllie, A.R.Johnston, D.Lipscombe, and P.E.Chen (2006).
Single-channel analysis of a point mutation of a conserved serine residue in the S2 ligand-binding domain of the NR2A NMDA receptor subunit.
  J Physiol, 574, 477-489.  
17057341 I.Huvent, H.Belrhali, R.Antoine, C.Bompard, C.Locht, F.Jacob-Dubuisson, and V.Villeret (2006).
Structural analysis of Bordetella pertussis BugE solute receptor in a bound conformation.
  Acta Crystallogr D Biol Crystallogr, 62, 1375-1381.
PDB code: 2dvz
16371009 J.A.Roberts, and R.J.Evans (2006).
Contribution of conserved polar glutamine, asparagine and threonine residues and glycosylation to agonist action at human P2X1 receptors for ATP.
  J Neurochem, 96, 843-852.  
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.  
16408092 M.Volgraf, P.Gorostiza, R.Numano, R.H.Kramer, E.Y.Isacoff, and D.Trauner (2006).
Allosteric control of an ionotropic glutamate receptor with an optical switch.
  Nat Chem Biol, 2, 47-52.  
16474411 P.E.Chen, and D.J.Wyllie (2006).
Pharmacological insights obtained from structure-function studies of ionotropic glutamate receptors.
  Br J Pharmacol, 147, 839-853.  
16847640 P.Pinheiro, and C.Mulle (2006).
Kainate receptors.
  Cell Tissue Res, 326, 457-482.  
16525550 U.Pentikäinen, L.Settimo, M.S.Johnson, and O.T.Pentikäinen (2006).
Subtype selectivity and flexibility of ionotropic glutamate receptors upon antagonist ligand binding.
  Org Biomol Chem, 4, 1058-1070.  
16281028 H.Furukawa, S.K.Singh, R.Mancusso, and E.Gouaux (2005).
Subunit arrangement and function in NMDA receptors.
  Nature, 438, 185-192.
PDB codes: 2a5s 2a5t 2ipv
15919192 M.L.Mayer (2005).
Glutamate receptor ion channels.
  Curr Opin Neurobiol, 15, 282-288.  
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.