7FH2

Crystal structure of the first bromodomain of BRD4 in complex with 16D10

7FH2 の概要

• エントリーDOI: 10.2210/pdb7fh2/pdb
• 分子名称: Bromodomain-containing protein 4, N-[2-[2-[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]-4,5-dimethoxy-phenyl]ethyl]ethanamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, bromodomain, brd4, histone, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 66437.92

構造登録者

Yokoyama, T.,Hirasawa, N. (登録日: 2021-07-29, 公開日: 2022-08-03, 最終更新日: 2023-11-29)

主引用文献

Segawa, R.,Takeda, H.,Yokoyama, T.,Ishida, M.,Miyata, C.,Saito, T.,Ishihara, R.,Nakagita, T.,Sasano, Y.,Kanoh, N.,Iwabuchi, Y.,Mizuguchi, M.,Hiratsuka, M.,Hirasawa, N.
A chalcone derivative suppresses TSLP induction in mice and human keratinocytes through binding to BET family proteins.
Biochem Pharmacol, 194:114819-114819, 2021

PubMed Abstract: Although treatments for allergic diseases have improved, side effects and treatment resistance remain as challenges. New therapeutic drugs for allergic diseases are urgently required. Thymic stromal lymphopoietin (TSLP) is a cytokine target for prevention and treatment of allergic diseases. Since TSLP is produced from epithelial cells in allergic diseases, TSLP inhibitors may be new anti-allergic drugs. We previously identified a new inhibitor of TSLP production, named 16D10. However, its target of action remained unclarified. In this study, we found proteins binding to 16D10 from 24,000 human protein arrays by AlphaScreen-based high-throughput screening and identified bromodomain and extra-terminal (BET) family proteins as targets. We also clarified the detailed mode of interaction between 16D10 and a BET family protein using X-ray crystallography. Furthermore, we confirmed that inhibitors of BET family proteins suppressed TSLP induction and IL-33 and IL-36γ expression in both mouse and human keratinocyte cell lines. Taken together, our findings suggest that BET family proteins are involved in the suppression of TSLP production by 16D10. These proteins can contribute to the pathology of atopic dermatitis via TSLP regulation in keratinocytes and have potential as therapeutic targets in allergic diseases.

PubMed: 34757034
DOI: 10.1016/j.bcp.2021.114819

実験手法

X-RAY DIFFRACTION (2.492 Å)