4BW2

The first bromodomain of human BRD4 in complex with 3,5 dimethylisoxaxole ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Naphthyridines as Novel Bet Family Bromodomain Inhibitors.

Mirguet, O.Lamotte, Y.Chung, C.Bamborough, P.Delannee, D.Bouillot, A.Gellibert, F.Krysa, G.Lewis, A.Witherington, J.Huet, P.Dudit, Y.Trottet, L.Nicodeme, E.

(2014) ChemMedChem 9: 589

  • DOI: https://doi.org/10.1002/cmdc.201300259
  • Primary Citation of Related Structures:  
    4BW1, 4BW2, 4BW3, 4BW4

  • PubMed Abstract: 

    Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.


  • Organizational Affiliation

    Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 Avenue du Québec, 91140 Villebon-sur-Yvette (France); Current address: Institut de Recherches Servier, 11 Rue des Moulineaux, 92150 Suresnes (France). oliviermirguet@yahoo.fr.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 4127Homo sapiensMutation(s): 0 
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
UTH
Query on UTH

Download Ideal Coordinates CCD File 
C [auth A]4-((2-(TERT-BUTYL)PHENYL)AMINO)-7-(3,5-dimethylisoxazol-4-yl)-1,8-naphthyridine-3-carboxylic acid
C24 H24 N4 O3
PTXRSHPWCLHNBN-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
UTH Binding MOAD:  4BW2 IC50: 6310 (nM) from 1 assay(s)
PDBBind:  4BW2 IC50: 6310 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.93α = 90
b = 47.86β = 90
c = 61.98γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-11
    Type: Initial release
  • Version 1.1: 2014-03-19
    Changes: Database references