PDB 4HBW deposited: 2012-09-28 modified: 2012-12-12
Title Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazoline ligand
Authors Bish, G., Brennan, P.E., Bunnage, M.E., Cook, A.S., Federov, O., Filippakopoulos, P., Fish, P.V., Gerstenberger, B.S., Jones, H., Knapp, S., Marsden, B., Nocka, K., Owen, D.R., Philpott, M., Picaud, S., Primiano, M.J., Ralph, M.J., Sciammetta, N., Trzupek, J.D.
Structure factors resolution None rfactor None rfree None
Related PDB Entries 4E96 4HBV 4HBX 4HBY

The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.

J.Med.Chem. 2012 Nov; 55(22):9831-9837 doi:10.1021/jm3010515

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL2177039
PubMed 23095041 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4HBW/0 4HBW 0 monomer 0 1 3 1181