5EA2

Crystal Structure of Holo NAD(P)H dehydrogenase, quinone 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

A direct interaction between NQO1 and a chemotherapeutic dimeric naphthoquinone.

Pidugu, L.S.Mbimba, J.C.Ahmad, M.Pozharski, E.Sausville, E.A.Emadi, A.Toth, E.A.

(2016) BMC Struct Biol 16: 1-1

  • DOI: https://doi.org/10.1186/s12900-016-0052-x
  • Primary Citation of Related Structures:  
    5EA2, 5EAI

  • PubMed Abstract: 

    Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these compounds hold great potential as therapeutic agents against highly proliferative neoplastic cells. In our previous work, we developed a series of novel dimeric naphthoquinones and showed that they were selectively cytotoxic to human acute myeloid leukemia (AML), breast and prostate cancer cell lines. We subsequently identified the oxidoreductase NAD(P)H dehydrogenase, quinone 1 (NQO1) as the major target of dimeric naphthoquinones and proposed a mechanism of action that entailed induction of a futile redox cycling. Here, for the first time, we describe a direct physical interaction between the bromohydroxy dimeric naphthoquinone E6a and NQO1. Moreover, our studies reveal an extensive binding interface between E6a and the isoalloxazine ring of the flavin adenine dinucleotide (FAD) cofactor of NQO1 in addition to interactions with protein side chains in the active site. We also present biochemical evidence that dimeric naphthoquinones affect the redox state of the FAD cofactor of NQO1. Comparison of the mode of binding of E6a with those of other chemotherapeutics reveals unique characteristics of the interaction that can be leveraged in future drug optimization efforts. The first structure of a dimeric naphthoquinone-NQO1 complex was reported, which can be used for design and synthesis of more potent next generation dimeric naphthoquinones to target NQO1 with higher affinity and specificity.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NAD(P)H dehydrogenase [quinone] 1A,
B [auth C],
C [auth E],
D [auth G]
276Homo 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.93α = 90
b = 107.16β = 100.68
c = 99.76γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
MOSFLMdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-02-10
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Advisory, Data collection, Derived calculations
  • Version 1.2: 2023-09-27
    Changes: Advisory, Data collection, Database references, Refinement description