7LA9

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

7LA9 の概要

• エントリーDOI: 10.2210/pdb7la9/pdb
• 分子名称: 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)
• 機能のキーワード: bet, erk5, dual brd-kinase inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 93193.37

構造登録者

Karim, M.R.,Schonbrunn, E. (登録日: 2021-01-06, 公開日: 2022-01-12, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.2 Å)