6FT4

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.34 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.169 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability.

Jennings, L.E.Schiedel, M.Hewings, D.S.Picaud, S.Laurin, C.M.C.Bruno, P.A.Bluck, J.P.Scorah, A.R.See, L.Reynolds, J.K.Moroglu, M.Mistry, I.N.Hicks, A.Guzanov, P.Clayton, J.Evans, C.N.G.Stazi, G.Biggin, P.C.Mapp, A.K.Hammond, E.M.Humphreys, P.G.Filippakopoulos, P.Conway, S.J.

(2018) Bioorg Med Chem 26: 2937-2957

  • DOI: https://doi.org/10.1016/j.bmc.2018.05.003
  • Primary Citation of Related Structures:  
    6FSY, 6FT3, 6FT4

  • PubMed Abstract: 

    Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t ½  = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC 50  = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t ½  = 388 min).


  • Organizational Affiliation

    Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
E5W
Query on E5W

Download Ideal Coordinates CCD File 
B [auth A]3-[[4,4-bis(fluoranyl)piperidin-1-yl]methyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenol
C17 H20 F2 N2 O2
ASWANVCVFDVNLN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
E5W BindingDB:  6FT4 IC50: min: 234, max: 235 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.34 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.665α = 90
b = 48.982β = 90
c = 60.494γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom095751/Z/11/Z

Revision History  (Full details and data files)

  • Version 1.0: 2018-04-18
    Type: Initial release
  • Version 1.1: 2019-04-24
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description