3GBA

X-ray structure of iGluR5 ligand-binding core (S1S2) in complex with dysiherbaine at 1.35A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.165 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

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

Frydenvang, K.Lash, L.L.Naur, P.Postila, P.A.Pickering, D.S.Smith, C.M.Gajhede, M.Sasaki, M.Sakai, R.Pentikainen, O.T.Swanson, G.T.Kastrup, J.S.

(2009) J Biol Chem 284: 14219-14229

  • DOI: https://doi.org/10.1074/jbc.M808547200
  • Primary Citation of Related Structures:  
    3GBA, 3GBB

  • PubMed Abstract: 

    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-dideoxyneodysiherbaine (MSVIII-19), induced a fully closed iGluR5 ligand-binding core. The degree of relative domain closure, approximately 30 degrees , was similar to that we resolved with the structurally related high affinity agonist dysiherbaine 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 (EC(50) = 3.6 microm) and on the nondesensitizing receptor mutant iGluR5-2b(Y506C/L768C) (EC(50) = 8.1 microm). 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 interdomain hydrogen bond residues Glu(441) and Ser(721) in the iGluR5-S1S2 structure. The weaker interactions of MSVIII-19 with iGluR5 compared with dysiherbaine, together with altered stability of the interdomain interaction, may be responsible for the apparent uncoupling of domain closure and channel opening in this kainate receptor subunit.


  • Organizational Affiliation

    Department of Medicinal Chemistry and Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor, ionotropic kainate 1
A, B, C, D
257Rattus norvegicusMutation(s): 0 
Gene Names: Glur5Grik1
UniProt
Find proteins for P22756 (Rattus norvegicus)
Explore P22756 
Go to UniProtKB:  P22756
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22756
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DYH
Query on DYH

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
M [auth C],
O [auth D]
(2R,3aR,6S,7R,7aR)-2-[(2S)-2-amino-2-carboxyethyl]-6-hydroxy-7-(methylamino)hexahydro-2H-furo[3,2-b]pyran-2-carboxylic acid
C12 H20 N2 O7
YUSZFKPLFIQTGF-FDNSHYBFSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B],
N [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
H [auth A],
L [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
DYH Binding MOAD:  3GBA Ki: 0.85 (nM) from 1 assay(s)
PDBBind:  3GBA Ki: 0.85 (nM) from 1 assay(s)
BindingDB:  3GBA Ki: 0.74 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.165 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.872α = 92.69
b = 66.902β = 94.66
c = 90.342γ = 100.82
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2017-08-16
    Changes: Data collection, Refinement description, Source and taxonomy
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Refinement description