3MXF

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JQ1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.150 
  • R-Value Observed: 0.151 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Selective inhibition of BET bromodomains.

Filippakopoulos, P.Qi, J.Picaud, S.Shen, Y.Smith, W.B.Fedorov, O.Morse, E.M.Keates, T.Hickman, T.T.Felletar, I.Philpott, M.Munro, S.McKeown, M.R.Wang, Y.Christie, A.L.West, N.Cameron, M.J.Schwartz, B.Heightman, T.D.La Thangue, N.French, C.A.Wiest, O.Kung, A.L.Knapp, S.Bradner, J.E.

(2010) Nature 468: 1067-1073

  • DOI: https://doi.org/10.1038/nature09504
  • Primary Citation of Related Structures:  
    3MXF, 3ONI

  • PubMed Abstract: 

    Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.


  • Organizational Affiliation

    Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, 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: BRD4HUNK1Mcap
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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JQ1
Query on JQ1

Download Ideal Coordinates CCD File 
B [auth A](6S)-6-(2-tert-butoxy-2-oxoethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6,7-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium
C23 H26 Cl N4 O2 S
DNVXATUJJDPFDM-KRWDZBQOSA-O
IOD
Query on IOD

Download Ideal Coordinates CCD File 
C [auth A]IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
DMS
Query on DMS

Download Ideal Coordinates CCD File 
G [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
JQ1 PDBBind:  3MXF Kd: 49 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.150 
  • R-Value Observed: 0.151 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.8α = 90
b = 44.76β = 90
c = 78.39γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
MOSFLMdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-10-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-03-28
    Changes: Structure summary
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description