4MEN

Crystal Structure of the first bromodomain of human BRD4 in complex with a 5-methyl-triazolopyrimidine ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening.

Vidler, L.R.Filippakopoulos, P.Fedorov, O.Picaud, S.Martin, S.Tomsett, M.Woodward, H.Brown, N.Knapp, S.Hoelder, S.

(2013) J Med Chem 56: 8073-8088

  • DOI: https://doi.org/10.1021/jm4011302
  • Primary Citation of Related Structures:  
    4MEN, 4MEO, 4MEP, 4MEQ

  • PubMed Abstract: 

    Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.


  • Organizational Affiliation

    Division of Cancer Therapeutics, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.


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
25K
Query on 25K

Download Ideal Coordinates CCD File 
C [auth A]N,5-dimethyl-N-(4-methylbenzyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
C15 H17 N5
JAEVUMCKPBRDAJ-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
25K PDBBind:  4MEN IC50: 1.25e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.166 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.519α = 90
b = 44.229β = 90
c = 78.02γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-25
    Type: Initial release
  • Version 1.1: 2013-10-30
    Changes: Database references
  • Version 1.2: 2014-02-19
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description