4J3I

X-ray crystal structure of bromodomain complex to 1.24 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.145 
  • R-Value Work: 0.113 
  • R-Value Observed: 0.115 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist.

McLure, K.G.Gesner, E.M.Tsujikawa, L.Kharenko, O.A.Attwell, S.Campeau, E.Wasiak, S.Stein, A.White, A.Fontano, E.Suto, R.K.Wong, N.C.Wagner, G.S.Hansen, H.C.Young, P.R.

(2013) PLoS One 8: e83190-e83190

  • DOI: https://doi.org/10.1371/journal.pone.0083190
  • Primary Citation of Related Structures:  
    4J1P, 4J3I

  • PubMed Abstract: 

    Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.


  • Organizational Affiliation

    Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.


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
1K0 BindingDB:  4J3I Kd: min: 130, max: 8930 (nM) from 7 assay(s)
IC50: min: 40, max: 1.00e+4 (nM) from 23 assay(s)
Binding MOAD:  4J3I Kd: 8930 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.145 
  • R-Value Work: 0.113 
  • R-Value Observed: 0.115 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.278α = 90
b = 44.623β = 90
c = 78.064γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-01-15
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description