5EAI

Crystal Structure of NAD(P)H dehydrogenase, quinone 1 complexed with a chemotherapeutic naphthoquinone E6a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

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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] 1
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L, M, N
277Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
AA [auth J]
BA [auth K]
DA [auth L]
EA [auth M]
GA [auth N]
AA [auth J],
BA [auth K],
DA [auth L],
EA [auth M],
GA [auth N],
O [auth A],
P [auth B],
R [auth C],
S [auth D],
T [auth E],
V [auth F],
W [auth G],
X [auth H],
Z [auth I]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
E6A
Query on E6A

Download Ideal Coordinates CCD File 
CA [auth K],
FA [auth M],
Q [auth B],
U [auth E],
Y [auth H]
(2~{R},3~{R})-2-[(2~{S},3~{S})-3-bromanyl-1,4-bis(oxidanylidene)-2,3-dihydronaphthalen-2-yl]-3-oxidanyl-2,3-dihydronaphthalene-1,4-dione
C20 H13 Br O5
OKRIVCINKCLENI-OHNQJVKOSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.6α = 90
b = 210.77β = 90
c = 228.08γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
Aimlessdata scaling
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: 2016-02-17
    Type: Initial release
  • Version 1.1: 2024-03-06
    Changes: Data collection, Database references, Derived calculations