3P5O

Crystal Structure of the First Bromodomain of Human Brd4 in complex with IBET inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.157 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Suppression of inflammation by a synthetic histone mimic

Nicodeme, E.Jeffrey, K.L.Schaefer, U.Beinke, S.Dewell, S.Chung, C.Chandwani, R.Marazzi, I.Wilson, P.Coste, H.White, J.Kirilovsky, J.Rice, C.M.Lora, J.M.Prinjha, R.K.Lee, K.Tarakhovsky, A.

(2010) Nature 468: 1119-1123

  • DOI: https://doi.org/10.1038/nature09589
  • Primary Citation of Related Structures:  
    3P5O

  • PubMed Abstract: 

    Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.


  • Organizational Affiliation

    Centre de Recherche GSK, 27 Avenue du Québec, 91140 Villebon Sur Yvette, France.


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
Binding Affinity Annotations 
IDSourceBinding Affinity
EAM BindingDB:  3P5O Ki: min: 23, max: 200 (nM) from 11 assay(s)
Kd: min: 19, max: 99 (nM) from 9 assay(s)
IC50: min: 20, max: 740 (nM) from 21 assay(s)
EC50: 440 (nM) from 1 assay(s)
Binding MOAD:  3P5O Kd: 55.2 (nM) from 1 assay(s)
PDBBind:  3P5O Kd: 50.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.157 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.428α = 90
b = 44.333β = 90
c = 78.345γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2010-11-17 
  • Deposition Author(s): Chung, C.

Revision History  (Full details and data files)

  • Version 1.0: 2010-11-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description