5Y1Y

Complex structure of nitroxoline with the first bromodomain of BRD4


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.184 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues.

Jiang, H.Xing, J.Wang, C.Zhang, H.Yue, L.Wan, X.Chen, W.Ding, H.Xie, Y.Tao, H.Chen, Z.Jiang, H.Chen, K.Chen, S.Zheng, M.Zhang, Y.Luo, C.

(2017) Org Biomol Chem 15: 9352-9361

  • DOI: https://doi.org/10.1039/c7ob02369c
  • Primary Citation of Related Structures:  
    5Y1Y

  • PubMed Abstract: 

    The BET family of bromodomain-containing proteins (BRDs) is believed to be a promising drug target for therapeutic intervention in a number of diseases including cancer, inflammation and cardiovascular diseases. Hence, there is a great demand for novel chemotypes of BET inhibitors. The drug repurposing strategy offers great benefits to find inhibitors with known safety and pharmacokinetic profiles, thus increasing medicinal chemists' interest in recent years. Using the drug repurposing strategy, a BRD4-specific score based virtual screening campaign on an in-house drug library was conducted followed by the ALPHA screen assay test. Nitroxoline, an FDA-approved antibiotic, was identified to effectively disrupt the interaction between the first bromodomain of BRD4 (bromodomain-containing protein 4) and acetylated H4 peptide with IC 50 of 0.98 μM. Nitroxoline inhibited all BET family members with good selectivity against non-BET bromodomain-containing proteins, thus it is defined as a selective BET inhibitor. Based on the crystal structure of the nitroxoline-BRD4_BD1 complex, the mechanism of action as well as BET specificity of nitroxoline were determined. Since the anticancer activity of nitroxoline against MLL leukemia, one of the BET related diseases, has not been studied before, we tested whether nitroxoline might serve as a potential repurposing drug candidate for MLL leukemia. Nitroxoline effectively inhibited the proliferation of MLL leukemia cells by inducing cell cycle arrest and apoptosis. The profound efficacy is, at least in part, due to the inhibition of BET and downregulation of target gene transcription. Our discovery of nitroxoline as a BET inhibitor suggests potential application of nitroxoline and its derivatives for clinical translation in BET family related diseases.


  • Organizational Affiliation

    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. zhangyy@simm.ac.cn myzheng@simm.ac.cn shijiechen@simm.ac.cn.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4125Homo sapiensMutation(s): 0 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HNQ
Query on HNQ

Download Ideal Coordinates CCD File 
B [auth A]5-nitroquinolin-8-ol
C9 H6 N2 O3
RJIWZDNTCBHXAL-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HNQ Binding MOAD:  5Y1Y IC50: 980 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.184 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.892α = 90
b = 47.298β = 90
c = 78.5γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
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: 2017-11-15
    Type: Initial release
  • Version 1.1: 2017-11-29
    Changes: Database references