7LA9

Crystal structure of the first bromodomain (BD1) of human BRD4 (BRD4-1) in complex with bivalent inhibitor NC-III-49-1

Summary for 7LA9

• Entry DOI: 10.2210/pdb7la9/pdb
• Descriptor: Bromodomain-containing protein 4, N,N'-(oxybis{(ethane-2,1-diyl)oxyethane-2,1-diyloxy[3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-4,1-phenylene]})di(ethane-1-sulfonamide), 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: bet, erk5, dual brd-kinase inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 93193.37

Authors

Karim, M.R.,Schonbrunn, E. (deposition date: 2021-01-06, release date: 2022-01-12, Last modification date: 2023-10-18)

Primary citation

Guan, X.,Cheryala, N.,Karim, R.M.,Chan, A.,Berndt, N.,Qi, J.,Georg, G.I.,Schonbrunn, E.
Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.
J.Med.Chem., 65:10441-10458, 2022

PubMed Abstract: Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization.

PubMed: 35867655
DOI: 10.1021/acs.jmedchem.2c00453

Experimental method

X-RAY DIFFRACTION (2.2 Å)