5ML0

Bromodomain of Mouse PCAF with (R)-4-chloro-2-methyl-5-((1-methylpiperidin-3-yl)amino)pyridazin-3(2H)-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


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
Histone acetyltransferase KAT2B110Mus musculusMutation(s): 0 
Gene Names: Kat2bPcaf
EC: 2.3.1.48
UniProt & NIH Common Fund Data Resources
Find proteins for Q9JHD1 (Mus musculus)
Explore Q9JHD1 
Go to UniProtKB:  Q9JHD1
IMPC:  MGI:1343094
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9JHD1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
P2L
Query on P2L

Download Ideal Coordinates CCD File 
B [auth A]4-chlorol-2-methyl-5-[[(3~{R})-1-methylpiperidin-3-yl]amino]pyridazin-3-one
C11 H17 Cl N4 O
LEPPHANDICKARV-MRVPVSSYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
P2L BindingDB:  5ML0 IC50: min: 85, max: 1259 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.481α = 90
b = 93.481β = 90
c = 32.783γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



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