PDBsum entry 1xan

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Glutathione reductase PDB id
Protein chain
461 a.a. *
Waters ×517
* Residue conservation analysis
PDB id:
Name: Glutathione reductase
Title: Human glutathione reductase in complex with a xanthene inhib
Structure: Glutathione reductase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
2.00Å     R-factor:   0.158    
Authors: S.N.Savvides,P.A.Karplus
Key ref: S.N.Savvides and P.A.Karplus (1996). Kinetics and crystallographic analysis of human glutathione reductase in complex with a xanthene inhibitor. J Biol Chem, 271, 8101-8107. PubMed id: 8626496
26-Jan-96     Release date:   11-Jul-96    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00390  (GSHR_HUMAN) -  Glutathione reductase, mitochondrial
522 a.a.
461 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Glutathione-disulfide reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 2 glutathione + NADP+ = glutathione disulfide + NADPH
2 × glutathione
+ NADP(+)
= glutathione disulfide
      Cofactor: FAD
Bound ligand (Het Group name = FAD) corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   3 terms 
  Biochemical function     oxidoreductase activity     5 terms  


J Biol Chem 271:8101-8107 (1996)
PubMed id: 8626496  
Kinetics and crystallographic analysis of human glutathione reductase in complex with a xanthene inhibitor.
S.N.Savvides, P.A.Karplus.
We have determined the crystal structure of a complex between the noncompetitive inhibitor (Kis = 27 microM, Kii = 48 microM with respect to oxidized glutathione (GSSG) and Kis = 144 microM, Kii = 176 microM with respect to NADPH) 6-hydroxy-3-oxo-3H-xanthene-9-propionic acid (XAN) and human glutathione reductase (hGR). The structure, refined to an R-factor of 0.158 at 2.0 A resolution, reveals XAN bound in the large cavity present at the hGR dimer interface where it does not overlap the glutathione binding site. The inhibitor binding causes extensive local structural changes that primarily involve amino acid residues from a 30-residue alpha-helix that lines the cavity and contributes to the active site of hGR. Despite the lack of physical overlap of XAN with the GSSG binding site, no GSSG binding is seen in soaks carried out with high XAN and GSSG concentrations, suggesting that some subtle interaction between the sites exists. An earlier crystallographic analysis on the complex between hGR and 3,7-diamino-2,8-dimethyl-5-phenyl-phenazinium chloride (safranin) showed that safranin bound at this same site. We have found that safranin also inhibits hGR in a noncompetitive fashion, but it binds about 16 times less tightly (Kis = 453 microM, Kii = 586 microM with respect to GSSG) than XAN and does not preclude the binding of GSSG in the crystal. Although in structure-based drug design competitive inhibitors are usually targetted, XAN's binding to a well defined site that is unique to glutathione reductase suggests that noncompetitive inhibitors could also serve as lead compounds for structure-based drug design, in particular as components of chimeric inhibitors.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19451637 L.Marty, W.Siala, M.Schwarzländer, M.D.Fricker, M.Wirtz, L.J.Sweetlove, Y.Meyer, A.J.Meyer, J.P.Reichheld, and R.Hell (2009).
The NADPH-dependent thioredoxin system constitutes a functional backup for cytosolic glutathione reductase in Arabidopsis.
  Proc Natl Acad Sci U S A, 106, 9109-9114.  
19049979 T.Seefeldt, Y.Zhao, W.Chen, A.S.Raza, L.Carlson, J.Herman, A.Stoebner, S.Hanson, R.Foll, and X.Guan (2009).
Characterization of a novel dithiocarbamate glutathione reductase inhibitor and its use as a tool to modulate intracellular glutathione.
  J Biol Chem, 284, 2729-2737.  
18638483 D.S.Berkholz, H.R.Faber, S.N.Savvides, and P.A.Karplus (2008).
Catalytic cycle of human glutathione reductase near 1 A resolution.
  J Mol Biol, 382, 371-384.
PDB codes: 3djg 3djj 3dk4 3dk8 3dk9
18300227 F.Angelucci, A.E.Miele, G.Boumis, D.Dimastrogiovanni, M.Brunori, and A.Bellelli (2008).
Glutathione reductase and thioredoxin reductase at the crossroad: the structure of Schistosoma mansoni thioredoxin glutathione reductase.
  Proteins, 72, 936-945.
PDB code: 2v6o
17918760 B.Stump, M.Kaiser, R.Brun, R.L.Krauth-Siegel, and F.Diederich (2007).
Betraying the Parasite's Redox System: Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties.
  ChemMedChem, 2, 1708-1712.  
17554778 J.Yu, and C.Z.Zhou (2007).
Crystal structure of glutathione reductase Glr1 from the yeast Saccharomyces cerevisiae.
  Proteins, 68, 972-979.
PDB code: 2hqm
16940112 K.M.Massimine, M.T.McIntosh, L.T.Doan, C.E.Atreya, S.Gromer, W.Sirawaraporn, D.A.Elliott, K.A.Joiner, R.H.Schirmer, and K.S.Anderson (2006).
Eosin B as a novel antimalarial agent for drug-resistant Plasmodium falciparum.
  Antimicrob Agents Chemother, 50, 3132-3141.  
16464233 M.L.Rathinam, L.T.Watts, A.A.Stark, L.Mahimainathan, J.Stewart, S.Schenker, and G.I.Henderson (2006).
Astrocyte control of fetal cortical neuron glutathione homeostasis: up-regulation by ethanol.
  J Neurochem, 96, 1289-1300.  
15657967 R.L.Krauth-Siegel, H.Bauer, and R.H.Schirmer (2005).
Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia.
  Angew Chem Int Ed Engl, 44, 690-715.  
12751785 K.Becker, S.Rahlfs, C.Nickel, and R.H.Schirmer (2003).
Glutathione--functions and metabolism in the malarial parasite Plasmodium falciparum.
  Biol Chem, 384, 551-566.  
11468346 N.Niccolai, R.Spadaccini, M.Scarselli, A.Bernini, O.Crescenzi, O.Spiga, A.Ciutti, D.Di Maro, L.Bracci, C.Dalvit, and P.A.Temussi (2001).
Probing the surface of a sweet protein: NMR study of MNEI with a paramagnetic probe.
  Protein Sci, 10, 1498-1507.  
9546215 K.Becker, S.N.Savvides, M.Keese, R.H.Schirmer, and P.A.Karplus (1998).
Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers.
  Nat Struct Biol, 5, 267-271.
PDB codes: 1dnc 1gsn
8879546 C.H.Faerman, S.N.Savvides, C.Strickland, M.A.Breidenbach, J.A.Ponasik, B.Ganem, D.Ripoll, R.L.Krauth-Siegel, and P.A.Karplus (1996).
Charge is the major discriminating factor for glutathione reductase versus trypanothione reductase inhibitors.
  Bioorg Med Chem, 4, 1247-1253.  
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.