4MR6

Crystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-208)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.157 

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This is version 1.2 of the entry. See complete history


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 2114Homo sapiensMutation(s): 0 
Gene Names: BRD2KIAA9001RING3
UniProt & NIH Common Fund Data Resources
Find proteins for P25440 (Homo sapiens)
Explore P25440 
Go to UniProtKB:  P25440
PHAROS:  P25440
GTEx:  ENSG00000204256 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25440
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1K0 PDBBind:  4MR6 Kd: 251 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.157 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.118α = 90
b = 52.692β = 90
c = 72.119γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
StructureStudiodata collection
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


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