6LLC

Discovery of A Dual Inhibitor of NQO1 and GSTP1 for Treating Malignant Glioblastoma


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma.

Lei, K.Gu, X.Alvarado, A.G.Du, Y.Luo, S.Ahn, E.H.Kang, S.S.Ji, B.Liu, X.Mao, H.Fu, H.Kornblum, H.I.Jin, L.Li, H.Ye, K.

(2020) J Hematol Oncol 13: 141-141

  • DOI: https://doi.org/10.1186/s13045-020-00979-y
  • Primary Citation of Related Structures:  
    6LLC, 6LLX

  • PubMed Abstract: 

    Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. We identified a small molecular inhibitor, "MNPC," that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.


  • Organizational Affiliation

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NAD(P)H dehydrogenase [quinone] 1
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L
273Homo sapiensMutation(s): 0 
Gene Names: NQO1DIA4NMOR1
EC: 1.6.5.2
UniProt & NIH Common Fund Data Resources
Find proteins for P15559 (Homo sapiens)
Explore P15559 
Go to UniProtKB:  P15559
PHAROS:  P15559
GTEx:  ENSG00000181019 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15559
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
BA [auth H]
CA [auth I]
FA [auth J]
HA [auth K]
JA [auth L]
BA [auth H],
CA [auth I],
FA [auth J],
HA [auth K],
JA [auth L],
M [auth A],
P [auth B],
R [auth C],
T [auth D],
V [auth E],
X [auth F],
Z [auth G]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
EHL (Subject of Investigation/LOI)
Query on EHL

Download Ideal Coordinates CCD File 
AA [auth H]
DA [auth I]
EA [auth J]
IA [auth L]
N [auth A]
AA [auth H],
DA [auth I],
EA [auth J],
IA [auth L],
N [auth A],
Q [auth B],
S [auth D],
W [auth E]
5-methyl-N-(5-nitro-1,3-thiazol-2-yl)-3-phenyl-1,2-oxazole-4-carboxamide
C14 H10 N4 O4 S
UYYQKLFHMYQRSN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
GA [auth J],
O [auth A],
U [auth D],
Y [auth F]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 147.882α = 90
b = 147.882β = 90
c = 209.791γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2020-11-25 
  • Deposition Author(s): Ye, K., Li, H.

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-25
    Type: Initial release
  • Version 1.1: 2023-11-22
    Changes: Advisory, Data collection, Database references, Refinement description