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PDBsum entry 3n9j

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
3n9j
Jmol
Contents
Protein chain
208 a.a.
Ligands
MES ×2
EAA ×2
Metals
_CA ×3
_PT
_CL
Waters ×377
PDB id:
3n9j
Name: Transferase
Title: Structure of human glutathione transferase pi class in compl ethacraplatin
Structure: Glutathione s-transferase p. Chain: a, b. Synonym: gst class-pi, gstp1-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: faees3, gst3, gstp1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.85Å     R-factor:   0.180     R-free:   0.218
Authors: L.J.Parker,M.W.Parker
Key ref: L.J.Parker et al. (2011). Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation. Chemistry, 17, 7806-7816. PubMed id: 21681839
Date:
30-May-10     Release date:   11-May-11    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P09211  (GSTP1_HUMAN) -  Glutathione S-transferase P
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 = HX + R-S-glutathione
RX
+ glutathione
= HX
+ R-S-glutathione
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     TRAF2-GSTP1 complex   9 terms 
  Biological process     metabolic process   31 terms 
  Biochemical function     S-nitrosoglutathione binding     8 terms  

 

 
    reference    
 
 
Chemistry 17:7806-7816 (2011)
PubMed id: 21681839  
 
 
Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation.
L.J.Parker, L.C.Italiano, C.J.Morton, N.C.Hancock, D.B.Ascher, J.B.Aitken, H.H.Harris, P.Campomanes, U.Rothlisberger, A.De Luca, M.Lo Bello, W.H.Ang, P.J.Dyson, M.W.Parker.
 
  ABSTRACT  
 
Platinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S-transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-Pt(IV) carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug-protein interactions between EA-CPT and GST P1-1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA-CPT preferentially docks at the dimer interface at GST P1-1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H-sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.