2YEM

Crystal Structure of the Second Bromodomain of Human Brd4 with the inhibitor GW841819X


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery and Characterization of Small Molecule Inhibitors of the Bet Family Bromodomains.

Chung, C.W.Coste, H.White, J.H.Mirguet, O.Wilde, J.Gosmini, R.L.Delves, C.Magny, S.M.Woodward, R.Hughes, S.A.Boursier, E.V.Flynn, H.Bouillot, A.M.Bamborough, P.Brusq, J.M.Gellibert, F.J.Jones, E.J.Riou, A.M.Homes, P.Martin, S.L.Uings, I.J.Toum, J.Clement, C.A.Boullay, A.B.Grimley, R.L.Blandel, F.M.Prinjha, R.K.Lee, K.Kirilovsky, J.Nicodeme, E.

(2011) J Med Chem 54: 3827

  • DOI: https://doi.org/10.1021/jm200108t
  • Primary Citation of Related Structures:  
    2YDW, 2YEK, 2YEL, 2YEM

  • PubMed Abstract: 

    Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.


  • Organizational Affiliation

    Molecular Discovery Research, GlaxoSmithKline R&D, Stevenage SG5 4HT, UK. Chun-Wa.H.Chung@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 4
A, B
130Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
WSH
Query on WSH

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
BENZYL [(4R)-1-METHYL-6-PHENYL-4H-[1,2,4]TRIAZOLO[4,3-A][1,4]BENZODIAZEPIN-4-YL]CARBAMATE
C25 H21 N5 O2
TUWDLUFFAHHNEF-QHCPKHFHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
WSH BindingDB:  2YEM Kd: min: 19, max: 52.5 (nM) from 3 assay(s)
IC50: min: 15.5, max: 501 (nM) from 4 assay(s)
Binding MOAD:  2YEM IC50: 15.5 (nM) from 1 assay(s)
PDBBind:  2YEM IC50: 15.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.674α = 90
b = 73.492β = 90
c = 74.362γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2011-06-15 
  • Deposition Author(s): Chung, C.W.

Revision History  (Full details and data files)

  • Version 1.0: 2011-06-15
    Type: Initial release
  • Version 1.1: 2013-05-08
    Changes: Structure summary
  • Version 1.2: 2019-08-21
    Changes: Data collection, Derived calculations
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description