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PDBsum entry 3gss
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protein ligands Protein-protein interface(s) links
Transferase PDB id
3gss

 

 

 

 

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Contents
Protein chain
208 a.a. *
Ligands
SO4
GSH-EAA ×2
MES ×2
Waters ×364
* Residue conservation analysis
PDB id:
3gss
Name: Transferase
Title: Human glutathione s-transferase p1-1 in complex with ethacrynic acid- glutathione conjugate
Structure: Glutathione s-transferase p1-1. Chain: a, b. Synonym: gst. Engineered: yes. Other_details: complexed with ethacrynic acid-glutathione conjugate
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: ubiquitous. Cellular_location: cytoplasm. Gene: gstp1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Homo-Dimer (from PDB file)
Resolution:
1.90Å     R-factor:   0.206     R-free:   0.233
Authors: A.J.Oakley,J.Rossjohn,M.W.Parker
Key ref:
A.J.Oakley et al. (1997). The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Biochemistry, 36, 576-585. PubMed id: 9012673 DOI: 10.1021/bi962316i
Date:
29-Oct-96     Release date:   12-Nov-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P09211  (GSTP1_HUMAN) -  Glutathione S-transferase P from Homo sapiens
Seq:
Struc: 		210 a.a.
208 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.5.1.18  - glutathione transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RX + glutathione = an S-substituted glutathione + a halide anion + H+
RX
Bound ligand (Het Group name = GSH)
corresponds exactly 		+ glutathione
 = S-substituted glutathione
 + halide anion
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1021/bi962316i Biochemistry 36:576-585 (1997)
PubMed id: 9012673  
 
 
The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate.
A.J.Oakley, J.Rossjohn, M.Lo Bello, A.M.Caccuri, G.Federici, M.W.Parker.
 
  ABSTRACT  
 
The potent diuretic drug ethacrynic acid has been tested in clinical trials as an adjuvant in chemotherapy. Its target is the detoxifying enzyme glutathione transferase which is often found overexpressed in cancer tissues. We have solved the crystal structures of human pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Ethacrynic acid is found to bind in a nonproductive mode to one of the ligand binding sites of the enzyme (the H site) while the glutathione binding site (G site) is occupied by solvent molecules. There are no structural rearrangements of the G site in the absence of ligand. The structure indicates that bound glutathione is required for ethacrynic acid to dock into the H site in a productive binding mode. The binding of the ethacrynic acid-glutathione conjugate shows that the contacts of the glutathione moiety with the protein are identical to those observed in crystal structures of the enzyme with other glutathione-based substrates and inhibitors. The ethacrynic acid moiety of the conjugate binds in the H site in a fashion that has not been observed in crystal structures of other glutathione-based inhibitor complexes. The crystal structures implicate Tyr 108 as an electrophilic participant in the Michael addition of glutathione to ethacrynic acid.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21428697 A.Oakley (2011).
Glutathione transferases: a structural perspective.
  Drug Metab Rev, 43, 138-151.  
21371745 G.Nocca, R.Ragno, V.Carbone, G.E.Martorana, D.V.Rossetti, G.Gambarini, B.Giardina, and A.Lupi (2011).
Identification of glutathione-methacrylates adducts in gingival fibroblasts and erythrocytes by HPLC-MS and capillary electrophoresis.
  Dent Mater, 27, e87-e98.  
20540076 I.Quesada-Soriano, L.J.Parker, A.Primavera, J.Wielens, J.K.Holien, J.M.Casas-Solvas, A.Vargas-Berenguel, A.M.Aguilera, M.Nuccetelli, A.P.Mazzetti, M.L.Bello, M.W.Parker, and L.García-Fuentes (2011).
Diuretic drug binding to human glutathione transferase P1-1: potential role of Cys-101 revealed in the double mutant C47S/Y108V.
  J Mol Recognit, 24, 220-234.
PDB codes: 3km6 3kmo
  21425928 J.U.Flanagan, and M.L.Smythe (2011).
Sigma-class glutathione transferases.
  Drug Metab Rev, 43, 194-214.  
  21401344 L.M.Balogh, and W.M.Atkins (2011).
Interactions of glutathione transferases with 4-hydroxynonenal.
  Drug Metab Rev, 43, 165-178.  
19780048 I.Quesada-Soriano, L.J.Parker, A.Primavera, J.M.Casas-Solvas, A.Vargas-Berenguel, C.Barón, C.J.Morton, A.Paola Mazzetti, M.Lo Bello, M.W.Parker, and L.García-Fuentes (2009).
Influence of the H-site residue 108 on human glutathione transferase P1-1 ligand binding: Structure-thermodynamic relationships and thermal stability.
  Protein Sci, 18, 2454-2470.
PDB codes: 3hjm 3hjo 3hkr
19323653 J.Wang, S.Wang, D.Song, D.Zhao, Y.Sha, Y.Jiang, Y.Jing, and M.Cheng (2009).
Chalcone derivatives inhibit glutathione S-transferase P1-1 activity: insights into the interaction mode of alpha, beta-unsaturated carbonyl compounds.
  Chem Biol Drug Des, 73, 511-514.  
18703268 N.Kinsley, Y.Sayed, S.Mosebi, R.N.Armstrong, and H.W.Dirr (2008).
Characterization of the binding of 8-anilinonaphthalene sulfonate to rat class Mu GST M1-1.
  Biophys Chem, 137, 100-104.  
19172745 T.Itoh, L.Fairall, K.Amin, Y.Inaba, A.Szanto, B.L.Balint, L.Nagy, K.Yamamoto, and J.W.Schwabe (2008).
Structural basis for the activation of PPARgamma by oxidized fatty acids.
  Nat Struct Mol Biol, 15, 924-931.
PDB codes: 2vsr 2vst 2vv0 2vv1 2vv2 2vv3 2vv4
16327895 C.J.Jackson, J.W.Liu, M.L.Coote, and D.L.Ollis (2005).
The effects of substrate orientation on the mechanism of a phosphotriesterase.
  Org Biomol Chem, 3, 4343-4350.  
15911318 G.Zhao, T.Yu, R.Wang, X.Wang, and Y.Jing (2005).
Synthesis and structure-activity relationship of ethacrynic acid analogues on glutathione-s-transferase P1-1 activity inhibition.
  Bioorg Med Chem, 13, 4056-4062.  
15906083 N.E.Labrou, M.Karavangeli, A.Tsaftaris, and Y.D.Clonis (2005).
Kinetic analysis of maize glutathione S-transferase I catalysing the detoxification from chloroacetanilide herbicides.
  Planta, 222, 91-97.  
14623980 K.Fritz-Wolf, A.Becker, S.Rahlfs, P.Harwaldt, R.H.Schirmer, W.Kabsch, and K.Becker (2003).
X-ray structure of glutathione S-transferase from the malarial parasite Plasmodium falciparum.
  Proc Natl Acad Sci U S A, 100, 13821-13826.
PDB code: 1okt
12596270 R.M.Cardoso, D.S.Daniels, C.M.Bruns, and J.A.Tainer (2003).
Characterization of the electrophile binding site and substrate binding mode of the 26-kDa glutathione S-transferase from Schistosoma japonicum.
  Proteins, 51, 137-146.
PDB codes: 1m99 1m9a 1m9b
11294649 M.Chang, Y.G.Shin, R.B.van Breemen, S.Y.Blond, and J.L.Bolton (2001).
Structural and functional consequences of inactivation of human glutathione S-transferase P1-1 mediated by the catechol metabolite of equine estrogens, 4-hydroxyequilenin.
  Biochemistry, 40, 4811-4820.  
10744339 A.J.Oakley, and M.C.Wilce (2000).
Macromolecular crystallography as a tool for investigating drug, enzyme and receptor interactions.
  Clin Exp Pharmacol Physiol, 27, 145-151.  
11123923 C.Micaloni, A.P.Mazzetti, M.Nuccetelli, J.Rossjohn, W.J.McKinstry, G.Antonini, A.M.Caccuri, A.J.Oakley, G.Federici, G.Ricci, M.W.Parker, and M.Lo Bello (2000).
Valine 10 may act as a driver for product release from the active site of human glutathione transferase P1-1.
  Biochemistry, 39, 15961-15970.  
10681528 J.Wang, S.Bauman, and R.F.Colman (2000).
Probing subunit interactions in alpha class rat liver glutathione S-transferase with the photoaffinity label glutathionyl S-[4-(succinimidyl)benzophenone].
  J Biol Chem, 275, 5493-5503.  
9665696 A.J.Oakley, M.Lo Bello, G.Ricci, G.Federici, and M.W.Parker (1998).
Evidence for an induced-fit mechanism operating in pi class glutathione transferases.
  Biochemistry, 37, 9912-9917.
PDB codes: 14gs 16gs
9843371 J.Wang, S.Bauman, and R.F.Colman (1998).
Photoaffinity labeling of rat liver glutathione S-transferase, 4-4, by glutathionyl S-[4-(succinimidyl)-benzophenone].
  Biochemistry, 37, 15671-15679.  
9446594 M.C.Vega, S.B.Walsh, T.J.Mantle, and M.Coll (1998).
The three-dimensional structure of Cys-47-modified mouse liver glutathione S-transferase P1-1. Carboxymethylation dramatically decreases the affinity for glutathione and is associated with a loss of electron density in the alphaB-310B region.
  J Biol Chem, 273, 2844-2850.
PDB codes: 1bay 1gti
9485454 M.Nicotra, M.Paci, M.Sette, A.J.Oakley, M.W.Parker, M.Lo Bello, A.M.Caccuri, G.Federici, and G.Ricci (1998).
Solution structure of glutathione bound to human glutathione transferase P1-1: comparison of NMR measurements with the crystal structure.
  Biochemistry, 37, 3020-3027.  
9818188 R.N.Armstrong (1998).
Mechanistic imperatives for the evolution of glutathione transferases.
  Curr Opin Chem Biol, 2, 618-623.  
9351803 L.Prade, R.Huber, T.H.Manoharan, W.E.Fahl, and W.Reuter (1997).
Structures of class pi glutathione S-transferase from human placenta in complex with substrate, transition-state analogue and inhibitor.
  Structure, 5, 1287-1295.
PDB codes: 1aqv 1aqw 1aqx
9166793 M.Lo Bello, A.J.Oakley, A.Battistoni, A.P.Mazzetti, M.Nuccetelli, G.Mazzarese, J.Rossjohn, M.W.Parker, and G.Ricci (1997).
Multifunctional role of Tyr 108 in the catalytic mechanism of human glutathione transferase P1-1. Crystallographic and kinetic studies on the Y108F mutant enzyme.
  Biochemistry, 36, 6207-6217.
PDB code: 4gss
9245401 X.Ji, M.Tordova, R.O'Donnell, J.F.Parsons, J.B.Hayden, G.L.Gilliland, and P.Zimniak (1997).
Structure and function of the xenobiotic substrate-binding site and location of a potential non-substrate-binding site in a class pi glutathione S-transferase.
  Biochemistry, 36, 9690-9702.
PDB codes: 1pgt 2pgt
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.

 

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