3JSX

X-ray Crystal structure of NAD(P)H: Quinone Oxidoreductase-1 (NQO1) bound to the coumarin-based inhibitor AS1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Synthesis and biological evaluation of coumarin-based inhibitors of NAD(P)H: quinone oxidoreductase-1 (NQO1).

Nolan, K.A.Doncaster, J.R.Dunstan, M.S.Scott, K.A.Frenkel, A.D.Siegel, D.Ross, D.Barnes, J.Levy, C.Leys, D.Whitehead, R.C.Stratford, I.J.Bryce, R.A.

(2009) J Med Chem 52: 7142-7156

  • DOI: https://doi.org/10.1021/jm9011609
  • Primary Citation of Related Structures:  
    3JSX

  • PubMed Abstract: 

    The synthesis is reported here of two novel series of inhibitors of human NAD(P)H quinone oxidoreductase-1 (NQO1), an enzyme overexpressed in several types of tumor cell. The first series comprises substituted symmetric dicoumarol analogues; the second series contains hybrid compounds where one 4-hydroxycoumarin system is replaced by a different aromatic moiety. Several compounds show equivalent or improved NQO1 inhibition over dicoumarol, both in the presence and in the absence of added protein. Further, correlation is demonstrated between the ability of these agents to inhibit NQO1 and computed binding affinity. We have solved the crystal structure of NQO1 complexed to a hybrid compound and find good agreement with the in silico model. For both MIA PaCa-2 pancreatic tumor cells and HCT116 colon cancer cells, dicoumarol shows the greatest toxicity of all compounds. Thus, we provide a computational, synthetic, and biological platform to generate competitive NQO1 inhibitors with superior pharmacological properties to dicoumarol. This will allow a more definitive study of NQO1 activity in cells, in particular, its drug activating/detoxifying properties and ability to modulate oncoprotein stability.


  • Organizational Affiliation

    School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester Cancer Research Center, Manchester, M13 9PT, United Kingdom.


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
273Homo sapiensMutation(s): 0 
Gene Names: DIA4NMOR1NQO1NQO1 cDNA
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
I [auth A]
K [auth B]
M [auth C]
O [auth D]
Q [auth E]
I [auth A],
K [auth B],
M [auth C],
O [auth D],
Q [auth E],
S [auth F],
U [auth G],
W [auth H]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
CC2
Query on CC2

Download Ideal Coordinates CCD File 
J [auth A]
L [auth B]
N [auth C]
P [auth D]
R [auth E]
J [auth A],
L [auth B],
N [auth C],
P [auth D],
R [auth E],
T [auth F],
V [auth G],
X [auth H]
4-hydroxy-6,7-dimethyl-3-(naphthalen-1-ylmethyl)-2H-chromen-2-one
C22 H18 O3
CLIXIKBUGAHFJT-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CC2 BindingDB:  3JSX IC50: min: 7.7, max: 1095 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.04α = 90
b = 209.94β = 109.93
c = 102.08γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
XSCALEdata 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: 2010-01-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2014-12-10
    Changes: Structure summary
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description