4O7C

Crystal structure of the first bromodomain of human BRD4 in complex with SB-614067-R

Summary for 4O7C

• Entry DOI: 10.2210/pdb4o7c/pdb
• Related: 4O70 4O71 4O72 4O73 4O74 4O75 4O76 4O77 4O78 4O7A 4O7B 4O7E 4O7F
• Descriptor: Bromodomain-containing protein 4, 4-[(5Z)-5-(1-nitroso-2,3-dihydro-5H-inden-5-ylidene)-2-(piperidin-4-yl)-3,5-dihydro-4H-imidazol-4-ylidene]-1,4-dihydropyridine, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain, cap, hunk1, mcap, protein binding-inhibitor complex, mitotic chromosome associated protein, cell cycle, inhibitor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15534.90

Authors

Ember, S.W.,Zhu, J.-Y.,Watts, C.,Schonbrunn, E. (deposition date: 2013-12-24, release date: 2014-03-05, Last modification date: 2023-09-20)

Primary citation

Ember, S.W.,Zhu, J.Y.,Olesen, S.H.,Martin, M.P.,Becker, A.,Berndt, N.,Georg, G.I.,Schonbrunn, E.
Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.
Acs Chem.Biol., 9:1160-1171, 2014

PubMed Abstract: Members of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation, and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential against BRD4 (IC50=25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site, suggesting that BET proteins are potential off-targets of diverse kinase inhibitors. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual-activity BET-kinase inhibitors.

PubMed: 24568369
DOI: 10.1021/cb500072z

Experimental method

X-RAY DIFFRACTION (1.55 Å)