4UIX

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 7-(3,4-dimethoxyphenyl)-N-(1,1-dioxo-1-thian-4-yl)-5-methyl-4-oxo-4H,5H-thieno-3,2-c-pyridine-2- carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.

Theodoulou, N.H.Bamborough, P.Bannister, A.J.Becher, I.Bit, R.A.Che, K.H.Chung, C.Dittmann, A.Drewes, G.Drewry, D.H.Gordon, L.Grandi, P.Leveridge, M.Lindon, M.Michon, A.Molnar, J.Robson, S.C.Tomkinson, N.C.O.Kouzarides, T.Prinjha, R.K.Humphreys, P.G.

(2016) J Med Chem 59: 1425

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00256
  • Primary Citation of Related Structures:  
    4UIT, 4UIU, 4UIV, 4UIW, 4UIX, 4UIY, 4UIZ

  • PubMed Abstract: 

    Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.


  • Organizational Affiliation

    Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 4
A, B, C
127Homo 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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TVU
Query on TVU

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
K [auth C]
N-[1,1-bis(oxidanylidene)thian-4-yl]-7-(3,4-dimethoxyphenyl)-5-methyl-4-oxidanylidene-thieno[3,2-c]pyridine-2-carboxamide
C22 H24 N2 O6 S2
ZJDRXPZROJHILR-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
J [auth C]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
TVU Binding MOAD:  4UIX IC50: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.64α = 90
b = 44.67β = 90.09
c = 77.55γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-22
    Type: Initial release
  • Version 1.1: 2016-03-09
    Changes: Database references
  • Version 1.2: 2017-09-27
    Changes: Data collection
  • Version 1.3: 2019-05-15
    Changes: Data collection, Experimental preparation