4UIT

BROMODOMAIN OF HUMAN BRD9 WITH 7-(3,4-dimethoxyphenyl)-2-(4- methanesulfonylpiperazine-1-carbonyl)-5-methyl-4H,5H-thieno-3,2-c- pyridin-4-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.152 
  • R-Value Observed: 0.153 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 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 9106Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H8M2 (Homo sapiens)
Explore Q9H8M2 
Go to UniProtKB:  Q9H8M2
PHAROS:  Q9H8M2
GTEx:  ENSG00000028310 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H8M2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
N1D
Query on N1D

Download Ideal Coordinates CCD File 
B [auth A]7-(3,4-dimethoxyphenyl)-5-methyl-2-(4-methylsulfonylpiperazin-1-yl)carbonyl-thieno[3,2-c]pyridin-4-one
C22 H25 N3 O6 S2
BEIFGZXXCPXAAY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
N1D Binding MOAD:  4UIT IC50: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.152 
  • R-Value Observed: 0.153 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 24.7α = 70.26
b = 34.11β = 73.8
c = 39.68γ = 74.24
Software Package:
Software NamePurpose
REFMACrefinement
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: 2019-05-15
    Changes: Advisory, Data collection, Experimental preparation, Other