4J0R

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.160 

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This is version 1.2 of the entry. See complete history


Literature

Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.

Hewings, D.S.Fedorov, O.Filippakopoulos, P.Martin, S.Picaud, S.Tumber, A.Wells, C.Olcina, M.M.Freeman, K.Gill, A.Ritchie, A.J.Sheppard, D.W.Russell, A.J.Hammond, E.M.Knapp, S.Brennan, P.E.Conway, S.J.

(2013) J Med Chem 56: 3217-3227

  • DOI: https://doi.org/10.1021/jm301588r
  • Primary Citation of Related Structures:  
    4J0R, 4J0S

  • PubMed Abstract: 

    The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.


  • Organizational Affiliation

    Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo 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
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1H2 BindingDB:  4J0R Kd: 360 (nM) from 1 assay(s)
IC50: 386 (nM) from 1 assay(s)
PDBBind:  4J0R IC50: 386 (nM) from 1 assay(s)
Binding MOAD:  4J0R IC50: 386 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.160 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.595α = 90
b = 42.856β = 90
c = 79.435γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-02-13
    Type: Initial release
  • Version 1.1: 2013-05-29
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description