6YB4

Crystal structure of human ATAD2 bromodomain in complex with N-(4-bromo-3-(3-methylpyrrolidin-1-yl)sulfonyl)phenyl)-2-(-4-cyclopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetamide

This is a non-PDB format compatible entry.

Summary for 6YB4

• Entry DOI: 10.2210/pdb6yb4/pdb
• Descriptor: ATPase family AAA domain-containing protein 2, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: inhibitor, atad2, bromodomain, epigenetics, atpase family aaa domain-containing protein 2, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16345.25

Authors

Chung, C. (deposition date: 2020-03-15, release date: 2020-05-06, Last modification date: 2024-05-15)

Primary citation

Lucas, S.C.C.,Atkinson, S.J.,Bamborough, P.,Barnett, H.,Chung, C.W.,Gordon, L.,Mitchell, D.J.,Phillipou, A.,Prinjha, R.K.,Sheppard, R.J.,Tomkinson, N.C.O.,Watson, R.J.,Demont, E.H.
Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode.
J.Med.Chem., 63:5212-5241, 2020

PubMed Abstract: Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.

PubMed: 32321240
DOI: 10.1021/acs.jmedchem.0c00021

Experimental method

X-RAY DIFFRACTION (1.85 Å)