3ZYU

Crystal Structure of the first bromodomain of human BRD4 in complex with I-BET151(GSK1210151A)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Inhibition of Bet Recruitment to Chromatin as an Effective Treatment for Mll-Fusion Leukaemia.

Dawson, M.A.Prinjha, R.K.Dittman, A.Giotopoulos, G.Bantscheff, M.Chan, W.I.Robson, S.C.Chung, C.W.Hopf, C.Savitski, M.M.Huthmacher, C.Gudgin, E.Lugo, D.Beinke, S.Chapman, T.D.Roberts, E.J.Soden, P.E.Auger, K.R.Mirguet, O.Doehner, K.Delwel, R.Burnett, A.K.Jeffrey, P.Drewes, G.Lee, K.Huntly, B.J.Kouzarides, T.

(2011) Nature 478: 529

  • DOI: https://doi.org/10.1038/nature10509
  • Primary Citation of Related Structures:  
    3ZYU

  • PubMed Abstract: 

    Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.


  • Organizational Affiliation

    Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0XY, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 4
A, B
127Homo sapiensMutation(s): 0 
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
1GH
Query on 1GH

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B]
7-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-8-METHOXY-1-[(1R)-1-(PYRIDIN-2-YL)ETHYL]-1H,2H,3H-IMIDAZO[4,5-C]QUINOLIN-2-ONE
C23 H21 N5 O3
VUVUVNZRUGEAHB-CYBMUJFWSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
H [auth B]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
H [auth B],
I [auth B],
J [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1GH BindingDB:  3ZYU Ki: min: 9, max: 385 (nM) from 4 assay(s)
Kd: min: 53, max: 215 (nM) from 2 assay(s)
IC50: min: 18, max: 794.33 (nM) from 13 assay(s)
PDBBind:  3ZYU Kd: 100 (nM) from 1 assay(s)
Binding MOAD:  3ZYU IC50: 100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.894α = 90
b = 59.542β = 90
c = 109.195γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
d*TREKdata reduction
d*TREKdata scaling
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: 2011-11-02
    Type: Initial release
  • Version 1.1: 2011-11-09
    Changes: Database references
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Other, Refinement description