PDBsum entry 3gba

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protein ligands metals Protein-protein interface(s) links
Membrane protein PDB id
Protein chains
257 a.a. *
DYH ×4
SO4 ×2
GOL ×3
_CL ×2
Waters ×1441
* Residue conservation analysis
PDB id:
Name: Membrane protein
Title: X-ray structure of iglur5 ligand-binding core (s1s2) in comp dysiherbaine at 1.35a resolution
Structure: Glutamate receptor, ionotropic kainate 1. Chain: a, b, c, d. Fragment: iglur5 ligand-binding core (s1s2). Synonym: glutamate receptor 5, glur-5, glur5. Engineered: yes
Source: Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: glur5, grik1. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.35Å     R-factor:   0.165     R-free:   0.193
Authors: K.Frydenvang,P.Naur,M.Gajhede,J.S.Kastrup
Key ref:
K.Frydenvang et al. (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 MSVIII-19. J Biol Chem, 284, 14219-14229. PubMed id: 19297335 DOI: 10.1074/jbc.M808547200
19-Feb-09     Release date:   17-Mar-09    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P22756  (GRIK1_RAT) -  Glutamate receptor ionotropic, kainate 1
949 a.a.
257 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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


DOI no: 10.1074/jbc.M808547200 J Biol Chem 284:14219-14229 (2009)
PubMed id: 19297335  
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 MSVIII-19.
K.Frydenvang, L.L.Lash, P.Naur, P.A.Postila, D.S.Pickering, C.M.Smith, M.Gajhede, M.Sasaki, R.Sakai, O.T.Pentikäinen, G.T.Swanson, J.S.Kastrup.
The prevailing structural model for ligand activation of ionotropic glutamate receptors posits that agonist efficacy arises from the stability and magnitude of induced domain closure in the ligand-binding core structure. Here we describe an exception to the correlation between ligand efficacy and domain closure. A weakly efficacious partial agonist of very low potency for homomeric iGluR5 kainate receptors, 8,9-dideoxy-neodysiherbaine (MSVIII-19), induced a fully closed iGluR5 ligand-binding core. The degree of relative domain closure, ~30 degrees , was similar to that we resolved with the structurally related high-affinity agonist dysiherbaine (DH), and to that of L-glutamate. The pharmacological activity of MSVIII-19 was confirmed in patch-clamp recordings from transfected HEK293 cells, where MSVIII-19 predominantly inhibits iGluR5-2a, with little activation apparent at a high concentration (1 mM) of MSVIII-19 (<1% of mean glutamate-evoked currents). To determine the efficacy of the ligand quantitatively, we constructed concentration-response relationships for MSVIII-19 following potentiation of steady-state currents with concanavalin A (EC50 3.6 muM) and on the non-desensitizing receptor mutant iGluR5-2b(Y506C/L768C) (EC50 8.1 muM). MSVIII-19 exhibited a maximum of 16% of full agonist efficacy as measured in parallel recordings with glutamate. Molecular dynamics simulations and electrophysiological recordings confirm that the specificity of MSVIII-19 for iGluR5 is partly attributable to inter-domain hydrogen bonds residues Glu441 and Ser721 in the iGluR5-S1S2 structure. The weaker interactions of MSVIII-19 with iGluR5 compared to DH, together with altered stability of the inter-domain interaction, may be responsible for the apparent uncoupling of domain closure and channel opening in this kainate receptor subunit.
  Selected figure(s)  
Figure 1.
Chemical structures of dysiherbaine and MSVIII-19. The two compounds differ in positions C8 (NH-Me substituent in DH versus H in MSVIII-19) and C9 (OH versus H).
Figure 3.
MSVIII-19 induces full domain closure in the ligand-binding core of iGluR5. A, superimposition of the MSVIII-19 (cyan), DH (yellow), and l-glutamate (Protein Data Bank code 1YCJ, molecule A; salmon) complexes with iGluR5-S1S2 on D1 residues. B, superimposition of the MSVIII-19 (cyan) and UBP302 (Protein Data Bank code 2F35, molecule A; blue) complexes with iGluR5-S1S2 on D1 residues. The high degree of domain closure introduced by MSVIII-19 compared with UBP302 is evident from the change of the D2 domain position.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2009, 284, 14219-14229) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21317895 A.Y.Lau, and B.Roux (2011).
The hidden energetics of ligand binding and activation in a glutamate receptor.
  Nat Struct Mol Biol, 18, 283-287.  
21324591 C.S.Qiu, L.Lash-Van Wyhe, M.Sasaki, R.Sakai, G.T.Swanson, and R.W.Gereau (2011).
Antinociceptive effects of MSVIII-19, a functional antagonist of the GluK1 kainate receptor.
  Pain, 152, 1052-1060.  
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
21349697 M.L.Mayer (2011).
Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation.
  Curr Opin Neurobiol, 21, 283-290.  
20673774 R.E.Hubbard (2011).
Structure-based drug discovery and protein targets in the CNS.
  Neuropharmacology, 60, 7.  
20107073 A.Birdsey-Benson, A.Gill, L.P.Henderson, and D.R.Madden (2010).
Enhanced efficacy without further cleft closure: reevaluating twist as a source of agonist efficacy in AMPA receptors.
  J Neurosci, 30, 1463-1470.
PDB codes: 3kei 3kfm
20436045 C.Shelley, and S.G.Cull-Candy (2010).
Desensitization and models of receptor-channel activation.
  J Physiol, 588, 1395-1397.  
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.  
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.