5MLI

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 4-chloro-2-methyl-5-(methylamino)pyridazin-3(2H)-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.190 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe.

Humphreys, P.G.Bamborough, P.Chung, C.W.Craggs, P.D.Gordon, L.Grandi, P.Hayhow, T.G.Hussain, J.Jones, K.L.Lindon, M.Michon, A.M.Renaux, J.F.Suckling, C.J.Tough, D.F.Prinjha, R.K.

(2017) J Med Chem 60: 695-709

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01566
  • Primary Citation of Related Structures:  
    5MKX, 5MKY, 5MKZ, 5ML0, 5MLI, 5MLJ

  • PubMed Abstract: 

    p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.


  • Organizational Affiliation

    Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline , Meyerhofstrasse 1, 69117 Heidelberg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
82I
Query on 82I

Download Ideal Coordinates CCD File 
B [auth A]4-chloranyl-2-methyl-5-(methylamino)pyridazin-3-one
C6 H8 Cl N3 O
ACZYSEPOODWZET-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
82I Binding MOAD:  5MLI IC50: 1.30e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.190 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.99α = 90
b = 41.86β = 90
c = 81.58γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-12-20 
  • Deposition Author(s): Chung, C.-W.

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-20
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Database references