5MGE

Crystal structure of BAZ2B bromodomain in complex with 1-methylpyridine derivative 1

5MGE の概要

• エントリーDOI: 10.2210/pdb5mge/pdb
• 分子名称: Bromodomain adjacent to zinc finger domain protein 2B, ethyl 4-chloranyl-1-methyl-6-oxidanylidene-pyridine-3-carboxylate (3 entities in total)
• 機能のキーワード: four helical bundle, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q9UIF8
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13747.21

構造登録者

Lolli, G.,Spiliotopoulos, D.,Caflisch, A. (登録日: 2016-11-21, 公開日: 2017-04-12, 最終更新日: 2024-01-17)

主引用文献

Spiliotopoulos, D.,Wamhoff, E.C.,Lolli, G.,Rademacher, C.,Caflisch, A.
Discovery of BAZ2A bromodomain ligands.
Eur J Med Chem, 139:564-572, 2017

PubMed Abstract: The bromodomain adjacent to zinc finger domain protein 2A (BAZ2A) is implicated in aggressive prostate cancer. The BAZ2A bromodomain is a challenging target because of the shallow pocket of its natural ligand, the acetylated side chain of lysine. Here, we report the successful screening of a library of nearly 1500 small molecules by high-throughput docking and force field-based binding-energy evaluation. For seven of the 20 molecules selected in silico, evidence of binding to the BAZ2A bromodomain is provided by ligand-observed NMR spectroscopy. Two of these compounds show a favorable ligand efficiency of 0.42 kcal/mol per non-hydrogen atom in a competition-binding assay. The crystal structures of the BAZ2A bromodomain in complex with four fragment hits validate the predicted binding modes. The binding modes of compounds 1 and 3 are compatible with ligand growing for optimization of affinity for BAZ2A and selectivity against the close homologue BAZ2B.

PubMed: 28837921
DOI: 10.1016/j.ejmech.2017.08.028

実験手法

X-RAY DIFFRACTION (1.95 Å)