5DW2

X-ray crystal structure of human BRD4(BD1) in complex with RVX297 to 1.12 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.12 Å
  • R-Value Free: 0.151 
  • R-Value Work: 0.123 
  • R-Value Observed: 0.124 

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This is version 1.2 of the entry. See complete history


Literature

RVX-297- a novel BD2 selective inhibitor of BET bromodomains.

Kharenko, O.A.Gesner, E.M.Patel, R.G.Norek, K.White, A.Fontano, E.Suto, R.K.Young, P.R.McLure, K.G.Hansen, H.C.

(2016) Biochem Biophys Res Commun 477: 62-67

  • DOI: https://doi.org/10.1016/j.bbrc.2016.06.021
  • Primary Citation of Related Structures:  
    5DW1, 5DW2

  • PubMed Abstract: 

    Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. We demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains.


  • Organizational Affiliation

    Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada. Electronic address: olesya@zenithepigenetics.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4129Homo 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
5GD Binding MOAD:  5DW2 Kd: 1440 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.12 Å
  • R-Value Free: 0.151 
  • R-Value Work: 0.123 
  • R-Value Observed: 0.124 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.279α = 90
b = 44.656β = 90
c = 78.015γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-06-22
    Type: Initial release
  • Version 1.1: 2016-07-20
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations