6E4A

Crystal structure of human BRD4(1) in complex with CN750


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.26 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery and lead identification of quinazoline-based BRD4 inhibitors.

Yang, S.M.Urban, D.J.Yoshioka, M.Strovel, J.W.Fletcher, S.Wang, A.Q.Xu, X.Shah, P.Hu, X.Hall, M.D.Jadhav, A.Maloney, D.J.

(2018) Bioorg Med Chem Lett 28: 3483-3488

  • DOI: https://doi.org/10.1016/j.bmcl.2018.08.039
  • Primary Citation of Related Structures:  
    6E4A

  • PubMed Abstract: 

    A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.


  • Organizational Affiliation

    National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States. Electronic address: yangs9@mail.nih.gov.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4
A, B
129Homo 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
HRY BindingDB:  6E4A Kd: min: 18, max: 50 (nM) from 3 assay(s)
Binding MOAD:  6E4A Kd: 44 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.26 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.163 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.477α = 90
b = 51.468β = 90.22
c = 55.297γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
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: 2018-09-12
    Type: Initial release
  • Version 1.1: 2018-10-03
    Changes: Data collection, Experimental preparation
  • Version 1.2: 2018-10-10
    Changes: Data collection, Database references, Structure summary
  • Version 1.3: 2018-10-24
    Changes: Data collection, Database references, Structure summary
  • Version 1.4: 2024-03-13
    Changes: Data collection, Database references