6CZU

BRD4(BD1) complexed with 3219


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.147 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Design and Characterization of Novel Covalent Bromodomain and Extra-Terminal Domain (BET) Inhibitors Targeting a Methionine.

Kharenko, O.A.Patel, R.G.Brown, S.D.Calosing, C.White, A.Lakshminarasimhan, D.Suto, R.K.Duffy, B.C.Kitchen, D.B.McLure, K.G.Hansen, H.C.van der Horst, E.H.Young, P.R.

(2018) J Med Chem 61: 8202-8211

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00666
  • Primary Citation of Related Structures:  
    6CZU, 6CZV

  • PubMed Abstract: 

    BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented noncovalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry, and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains and provide durable transcriptional and antiproliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.


  • Organizational Affiliation

    Zenith Epigenetics , Suite 300, 4820 Richard Road SW , Calgary , Alberta T3E 6L1 , Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4129Homo 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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FP7
Query on FP7

Download Ideal Coordinates CCD File 
B [auth A]5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-({4-[(1R)-1-hydroxyethyl]phenyl}methyl)pyridin-2(1H)-one
C19 H20 N2 O3
GYFSAKAXGZYFTD-CYBMUJFWSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
F [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
G [auth A]
H [auth A]
C [auth A],
D [auth A],
E [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.147 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.066α = 90
b = 48.967β = 90
c = 59.88γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-26
    Type: Initial release
  • Version 1.1: 2018-10-10
    Changes: Data collection, Database references