4MR3

Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolinone ligand (RVX-OH)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.142 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history

Re-refinement Note

This entry reflects an alternative modeling of the original data in: 4MR4


Literature

RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.

Picaud, S.Wells, C.Felletar, I.Brotherton, D.Martin, S.Savitsky, P.Diez-Dacal, B.Philpott, M.Bountra, C.Lingard, H.Fedorov, O.Muller, S.Brennan, P.E.Knapp, S.Filippakopoulos, P.

(2013) Proc Natl Acad Sci U S A 110: 19754-19759

  • DOI: https://doi.org/10.1073/pnas.1310658110
  • Primary Citation of Related Structures:  
    4MR3, 4MR4, 4MR5, 4MR6

  • PubMed Abstract: 

    Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation.


  • Organizational Affiliation

    Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.


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
1K0
Query on 1K0

Download Ideal Coordinates CCD File 
C [auth A]2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one
C20 H22 N2 O5
NETXMUIMUZJUTB-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1K0 BindingDB:  4MR3 Kd: min: 130, max: 8930 (nM) from 7 assay(s)
IC50: min: 40, max: 1.00e+4 (nM) from 23 assay(s)
PDBBind:  4MR3 Kd: 1142 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.142 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.74α = 90
b = 51.972β = 90
c = 57.539γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
StructureStudiodata collection
XDSdata reduction

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-11-27
    Type: Initial release
  • Version 1.1: 2014-01-22
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description