3GUR

Crystal Structure of mu class glutathione S-transferase (GSTM2-2) in complex with glutathione and 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.216 

Starting Model: experimental
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This is version 1.4 of the entry. See complete history


Literature

Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol to human glutathione s-transferases

Federici, L.Lo Sterzo, C.Pezzola, S.Di Matteo, A.Scaloni, F.Federici, G.Caccuri, A.M.

(2009) Cancer Res 69: 8025-8034

  • DOI: https://doi.org/10.1158/0008-5472.CAN-09-1314
  • Primary Citation of Related Structures:  
    3GUR, 3GUS, 3IE3

  • PubMed 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.


  • Organizational Affiliation

    Department of Biomedical Sciences, University of Chieti, CeSI Center of Excellence on Aging, G D'Annunzio University Foundation, Chieti, Italy. [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutathione S-transferase Mu 2
A, B, C, D
217Homo sapiensMutation(s): 0 
EC: 2.5.1.18
UniProt & NIH Common Fund Data Resources
Find proteins for P28161 (Homo sapiens)
Explore P28161 
Go to UniProtKB:  P28161
PHAROS:  P28161
GTEx:  ENSG00000213366 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28161
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
BYG PDBBind:  3GUR IC50: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.216 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.75α = 90
b = 78.016β = 90
c = 219.362γ = 90
Software Package:
Software NamePurpose
MAR345data collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-10-27
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-12-14
    Changes: Non-polymer description, Structure summary
  • Version 1.3: 2017-11-01
    Changes: Refinement description
  • Version 1.4: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description