4YQV

Glutathione S-transferase Omega 1 bound to covalent inhibitor C4-10


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.06 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor.

Ramkumar, K.Samanta, S.Kyani, A.Yang, S.Tamura, S.Ziemke, E.Stuckey, J.A.Li, S.Chinnaswamy, K.Otake, H.Debnath, B.Yarovenko, V.Sebolt-Leopold, J.S.Ljungman, M.Neamati, N.

(2016) Nat Commun 7: 13084-13084

  • DOI: https://doi.org/10.1038/ncomms13084
  • Primary Citation of Related Structures:  
    4YQM, 4YQU, 4YQV

  • PubMed Abstract: 

    Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology. We report on the development and characterization of a series of chloroacetamide-containing potent GSTO1 inhibitors. Co-crystal structures of GSTO1 with our inhibitors demonstrate covalent binding to the active site cysteine. These potent GSTO1 inhibitors suppress cancer cell growth, enhance the cytotoxic effects of cisplatin and inhibit tumour growth in colon cancer models as single agent. Bru-seq-based transcription profiling unravelled novel roles for GSTO1 in cholesterol metabolism, oxidative and endoplasmic stress responses, cytoskeleton and cell migration. Our findings demonstrate the therapeutic utility of GSTO1 inhibitors as anticancer agents and identify the novel cellular pathways under GSTO1 regulation in colorectal cancer.


  • Organizational Affiliation

    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90033, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutathione S-transferase omega-1
A, B, C
244Homo sapiensMutation(s): 0 
Gene Names: GSTO1GSTTLP28
EC: 2.5.1.18 (PDB Primary Data), 1.8.5.1 (PDB Primary Data), 1.20.4.2 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P78417 (Homo sapiens)
Explore P78417 
Go to UniProtKB:  P78417
PHAROS:  P78417
GTEx:  ENSG00000148834 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP78417
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.06 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 186.32α = 90
b = 71.373β = 105.16
c = 61.968γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACTdata extraction
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-10-12
    Type: Initial release
  • Version 1.1: 2016-10-19
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description