4QB3

Crystal structure of the first bromodomain of human BRD4 in complex with Olinone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.94 Å
  • R-Value Free: 0.155 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.137 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression.

Gacias, M.Gerona-Navarro, G.Plotnikov, A.N.Zhang, G.Zeng, L.Kaur, J.Moy, G.Rusinova, E.Rodriguez, Y.Matikainen, B.Vincek, A.Joshua, J.Casaccia, P.Zhou, M.M.

(2014) Chem Biol 21: 841-854

  • DOI: https://doi.org/10.1016/j.chembiol.2014.05.009
  • Primary Citation of Related Structures:  
    4QB3

  • PubMed Abstract: 

    Lysine acetylation regulates gene expression through modulating protein-protein interactions in chromatin. Chemical inhibition of acetyl-lysine binding bromodomains of the major chromatin regulators BET (bromodomain and extraterminal domain) proteins has been shown to effectively block cell proliferation in cancer and inflammation. However, whether selective inhibition of individual BET bromodomains has distinctive functional consequences remains only partially understood. In this study, we show that selective chemical inhibition of the first bromodomain of BET proteins using our small-molecule inhibitor, Olinone, accelerated the progression of mouse primary oligodendrocyte progenitors toward differentiation, whereas inhibition of both bromodomains of BET proteins hindered differentiation. This effect was target specific, as it was not detected in cells treated with inactive analogs and independent of any effect on proliferation. Therefore, selective chemical modulation of individual bromodomains, rather than use of broad-based inhibitors, may enhance regenerative strategies in disorders characterized by myelin loss such as aging and neurodegeneration.


  • Organizational Affiliation

    Departments of Neuroscience, and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.


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
30M
Query on 30M

Download Ideal Coordinates CCD File 
B [auth A]N-[4-(1-oxo-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)butyl]acetamide
C17 H21 N3 O2
RYVLOOXFFIFQEN-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
30M BindingDB:  4QB3 Ki: 1.72e+4 (nM) from 1 assay(s)
Kd: min: 3300, max: 3.00e+5 (nM) from 4 assay(s)
Binding MOAD:  4QB3 Kd: 3400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.94 Å
  • R-Value Free: 0.155 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.137 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.943α = 90
b = 44.126β = 90
c = 78.455γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-22
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description