7VS0

crystal structure of BRD2-BD2 in complex with purine derivative

7VS0 の概要

• エントリーDOI: 10.2210/pdb7vs0/pdb
• 分子名称: Bromodomain-containing protein 2, Doxofylline, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: bet family, bet inhibitor, bromodomain inhibitor, brd2-bd1 inhibitor, transcription, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14149.07

構造登録者

Padmanabhan, B.,Arole, A.,Deshmukh, P.,Ashok, S.,Mathur, S. (登録日: 2021-10-25, 公開日: 2023-02-01, 最終更新日: 2023-11-29)

主引用文献

Arole, A.H.,Deshmukh, P.,Sridhar, A.,Mathur, S.,Mahalingaswamy, M.,Subramanya, H.,Dalavaikodihalli Nanjaiah, N.,Padmanabhan, B.
Structural and biochemical insights into purine-based drug molecules in hBRD2 delineate a unique binding mode opening new vistas in the design of inhibitors of the BET family.
Acta Crystallogr D Struct Biol, 79:758-774, 2023

PubMed Abstract: The bromodomain and extra-terminal (BET) family proteins, which are involved in chromatin function, have been shown to be promising drug targets in several pathological conditions, including cancer and inflammation. There is considerable interest in the development of BET inhibitors with novel scaffolds to modulate the epigenesis of such diseases. Here, high-resolution crystal structures of the purine class of FDA-approved drugs (theophylline, doxophylline and acyclovir) and non-FDA-approved compounds (3-methyl-7-propylxanthine and theobromine) complexed with hBRD2 bromodomains BD1 and BD2 are reported. Remarkably, a new binding site is exhibited by stacking the compounds against the WPF shelf of BD1 and BD2. This serendipitous binding, in addition to the known acetyl-lysine binding site, sufficiently anchors the ligands in the solvent-exposed region. In addition, slight variations in the lipophilicity of these molecules significantly affected the in vitro binding affinity and selectivity towards BD1 compared with BD2. This idiosyncratic binding provides a new structural framework to link these sites for the development of next-generation inhibitors of the BET family.

PubMed: 37432115
DOI: 10.1107/S2059798323005211

実験手法

X-RAY DIFFRACTION (1.25 Å)