7FH2
Crystal structure of the first bromodomain of BRD4 in complex with 16D10
Summary for 7FH2
| Entry DOI | 10.2210/pdb7fh2/pdb |
| Descriptor | 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) |
| Functional Keywords | inhibitor, bromodomain, brd4, histone, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 66437.92 |
| Authors | Yokoyama, T.,Hirasawa, N. (deposition date: 2021-07-29, release date: 2022-08-03, Last modification date: 2023-11-29) |
| Primary citation | 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 Cited by 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: 34757034DOI: 10.1016/j.bcp.2021.114819 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.492 Å) |
Structure validation
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