4PCE

Crystal Structure of the first bromodomain of human BRD4 in complex with compound B13


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.29 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.137 
  • R-Value Observed: 0.138 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking.

Zhao, H.Gartenmann, L.Dong, J.Spiliotopoulos, D.Caflisch, A.

(2014) Bioorg Med Chem Lett 24: 2493-2496

  • DOI: https://doi.org/10.1016/j.bmcl.2014.04.017
  • Primary Citation of Related Structures:  
    4PCE, 4PCI

  • PubMed Abstract: 

    Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. BRD4, a protein containing two bromodomains, has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that bind to the first bromodomain of BRD4 with low-micromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non-hydrogen atom), selectively over other families of bromodomains. Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 9 million molecules, were tested in vitro.


  • Organizational Affiliation

    Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: h.zhao@bioc.uzh.ch.


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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2N0
Query on 2N0

Download Ideal Coordinates CCD File 
C [auth A]1-benzyl-2-ethyl-1,5,6,7-tetrahydro-4H-indol-4-one
C17 H19 N O
WAZKIRPFJTZRDA-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2N0 BindingDB:  4PCE IC50: 7000 (nM) from 1 assay(s)
Binding MOAD:  4PCE IC50: 7000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.29 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.137 
  • R-Value Observed: 0.138 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.59α = 90
b = 44.279β = 90
c = 78.371γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
SCALAdata scaling
XDSdata scaling
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-05-07
    Type: Initial release
  • Version 1.1: 2014-05-21
    Changes: Database references
  • Version 1.2: 2014-06-04
    Changes: Data collection, Database references
  • Version 1.3: 2015-02-04
    Changes: Derived calculations
  • Version 1.4: 2017-11-22
    Changes: Advisory, Database references, Derived calculations, Other, Refinement description, Source and taxonomy
  • Version 1.5: 2023-12-27
    Changes: Advisory, Data collection, Database references, Refinement description