5MLJ
Bromodomain of Human GCN5 with 4-bromo-2-methyl-5-(((3R,5R)-1-methyl-5-phenylpiperidin-3-yl)amino)pyridazin-3(2H)-one
Summary for 5MLJ
Entry DOI | 10.2210/pdb5mlj/pdb |
Descriptor | Histone acetyltransferase KAT2A, 1,2-ETHANEDIOL, 4-bromo-2-methyl-5-[[(3~{R},5~{R})-1-methyl-5-phenyl-piperidin-3-yl]amino]pyridazin-3-one, ... (4 entities in total) |
Functional Keywords | inhibitor, histone, epigenetic reader, bromodomain, gcn5, kat2a, antagonist, transcription |
Biological source | Homo sapiens (Human) |
Cellular location | Nucleus : Q92830 |
Total number of polymer chains | 2 |
Total formula weight | 27453.32 |
Authors | Chung, C.-W. (deposition date: 2016-12-06, release date: 2017-12-20, Last modification date: 2024-05-08) |
Primary citation | 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. Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe. J. Med. Chem., 60:695-709, 2017 Cited by 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. PubMed: 28002667DOI: 10.1021/acs.jmedchem.6b01566 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
Download full validation report