5MKX

1.68A STRUCTURE PCAF BROMODOMAIN WITH 4-chloro-2-methyl-5-(methylamino)pyridazin-3(2H)-one

5MKX の概要

• エントリーDOI: 10.2210/pdb5mkx/pdb
• 分子名称: Histone acetyltransferase KAT2B, 4-chloranyl-2-methyl-5-(methylamino)pyridazin-3-one, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: inhibitor, histone, epigenetic reader, bromodomain, pcaf, antagonist, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q92831
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29116.43

構造登録者

Chung, C.-W. (登録日: 2016-12-05, 公開日: 2017-12-20, 最終更新日: 2024-06-19)

主引用文献

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

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: 28002667
DOI: 10.1021/acs.jmedchem.6b01566

実験手法

X-RAY DIFFRACTION (1.68 Å)