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PDBsum entry 3gur

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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
3gur
Jmol
Contents
Protein chain
217 a.a. *
Ligands
BYG ×2
GSH ×2
EDO
Waters ×167
* Residue conservation analysis
PDB id:
3gur
Name: Transferase/transferase inhibitor
Title: Crystal structure of mu class glutathione s-transferase (gst complex with glutathione and 6-(7-nitro-2,1,3-benzoxadiazol ylthio)hexanol (nbdhex)
Structure: Glutathione s-transferase mu 2. Chain: a, b, c, d. Synonym: gstm2-2, gst class-mu 2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.50Å     R-factor:   0.216     R-free:   0.273
Authors: L.Federici,C.Lo Sterzo,A.Di Matteo,F.Scaloni,G.Federici,A.M.
Key ref: L.Federici et al. (2009). Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol to human glutathione s-transferases. Cancer Res, 69, 8025-8034. PubMed id: 19808963 DOI: 10.1158/0008-5472.CAN-09-1314
Date:
30-Mar-09     Release date:   27-Oct-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P28161  (GSTM2_HUMAN) -  Glutathione S-transferase Mu 2
Seq:
Struc:
218 a.a.
217 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
Bound ligand (Het Group name = BYG)
matches with 50.00% similarity
= 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     cytoplasm   4 terms 
  Biological process     metabolic process   15 terms 
  Biochemical function     transferase activity     6 terms  

 

 
    reference    
 
 
DOI no: 10.1158/0008-5472.CAN-09-1314 Cancer Res 69:8025-8034 (2009)
PubMed id: 19808963  
 
 
Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol to human glutathione s-transferases.
L.Federici, C.Lo Sterzo, S.Pezzola, A.Di Matteo, F.Scaloni, G.Federici, A.M.Caccuri.
 
  ABSTRACT  
 
Glutathione S-transferases (GST) constitute a superfamily of enzymes with diversified functions including detoxification from xenobiotics. In many human cancers, Pi class GST (GSTP1-1) is overexpressed and contributes to multidrug resistance by conjugating chemotherapeutics. In addition, GSTP1-1 displays antiapoptotic activity by interacting with c-Jun NH(2)-terminal kinase, a key regulator of apoptosis. Therefore, GSTP1-1 is considered a promising target for pharmaceutical treatment. Recently, a potent inhibitor of GSTs, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), was identified and tested on several tumor cell lines demonstrating high antiproliferative activity. To establish the structural basis of NBDHEX activity, we determined the crystal structure of NBDHEX bound to either GSTP1-1 or GSTM2-2 (mu class). NBDHEX in both cases binds to the H-site but occupies different positions. Furthermore, the compound is covalently attached to the GSH sulfur in the GSTM2-2 crystal, forming a sigma-complex, although it is bound but not conjugated in the GSTP1-1 crystal. Several differences in the H-sites of the two isozymes determine the higher affinity of NBDHEX for GSTM2-2 with respect to GSTP1-1. One such difference is the presence of Ile(104) in GSTP1-1 close to the bound NBDHEX, whereas the corresponding position is occupied by an alanine in GSTM2-2. Mutation of Ile(104) into valine is a frequent GSTP1-1 polymorphism and we show here that the Ile(104)Val and Ile(104)Ala variants display a 4-fold higher affinity for the compound. Remarkably, the GSTP1-1/Ile(104)Ala structure in complex with NBDHEX shows a considerable shift of the compound inside the H-site. These data might be useful for the development of new anticancer compounds.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20596078 E.Laborde (2010).
Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death.
  Cell Death Differ, 17, 1373-1380.  
20663851 L.Federici, M.Masulli, C.Di Ilio, and N.Allocati (2010).
Characterization of the hydrophobic substrate-binding site of the bacterial beta class glutathione transferase from Proteus mirabilis.
  Protein Eng Des Sel, 23, 743-750.  
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.