6DHL

Bovine glutamate dehydrogenase complexed with epicatechin-3-gallate (ECG)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.62 Å
  • R-Value Free: 0.314 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.249 

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Ligand Structure Quality Assessment 


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Literature

Green tea polyphenols control dysregulated glutamate dehydrogenase in transgenic mice by hijacking the ADP activation site.

Li, C.Li, M.Chen, P.Narayan, S.Matschinsky, F.M.Bennett, M.J.Stanley, C.A.Smith, T.J.

(2011) J Biol Chem 286: 34164-34174

  • DOI: https://doi.org/10.1074/jbc.M111.268599
  • Primary Citation of Related Structures:  
    6DHL

  • PubMed Abstract: 

    Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate and, in animals, is extensively regulated by a number of metabolites. Gain of function mutations in GDH that abrogate GTP inhibition cause the hyperinsulinism/hyperammonemia syndrome (HHS), resulting in increased pancreatic β-cell responsiveness to leucine and susceptibility to hypoglycemia following high protein meals. We have previously shown that two of the polyphenols from green tea (epigallocatechin gallate (EGCG) and epicatechin gallate (ECG)) inhibit GDH in vitro and that EGCG blocks GDH-mediated insulin secretion in wild type rat islets. Using structural and site-directed mutagenesis studies, we demonstrate that ECG binds to the same site as the allosteric regulator, ADP. Perifusion assays using pancreatic islets from transgenic mice expressing a human HHS form of GDH demonstrate that the hyperresponse to glutamine caused by dysregulated GDH is blocked by the addition of EGCG. As observed in HHS patients, these transgenic mice are hypersensitive to amino acid feeding, and this is abrogated by oral administration of EGCG prior to challenge. Finally, the low basal blood glucose level in the HHS mouse model is improved upon chronic administration of EGCG. These results suggest that this common natural product or some derivative thereof may prove useful in controlling this genetic disorder. Of broader clinical implication is that other groups have shown that restriction of glutamine catabolism via these GDH inhibitors can be useful in treating various tumors. This HHS transgenic mouse model offers a highly useful means to test these agents in vivo.


  • Organizational Affiliation

    Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate dehydrogenase 1, mitochondrial
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L
496Bos taurusMutation(s): 0 
EC: 1.4.1.2
UniProt
Find proteins for P00366 (Bos taurus)
Explore P00366 
Go to UniProtKB:  P00366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00366
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
XEG
Query on XEG

Download Ideal Coordinates CCD File 
M [auth A]
N [auth B]
O [auth C]
P [auth D]
Q [auth E]
M [auth A],
N [auth B],
O [auth C],
P [auth D],
Q [auth E],
R [auth F],
S [auth G],
T [auth H],
U [auth I],
V [auth J],
W [auth K],
X [auth L]
(2R,3S)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoate
C22 H18 O10
LSHVYAFMTMFKBA-PZJWPPBQSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.62 Å
  • R-Value Free: 0.314 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.249 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.12α = 90
b = 433.18β = 118.74
c = 95.17γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
SCALEPACKdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2018-07-25 
  • Deposition Author(s): Smith, T.J.
  • This entry supersedes: 3QMU

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-25
    Type: Initial release