5AYF
Crystal structure of SET7/9 in complex with cyproheptadine
Summary for 5AYF
| Entry DOI | 10.2210/pdb5ayf/pdb |
| Descriptor | Histone-lysine N-methyltransferase SETD7, S-ADENOSYLMETHIONINE, 4-(dibenzo[1,2-a:2',1'-d][7]annulen-11-ylidene)-1-methyl-piperidine, ... (5 entities in total) |
| Functional Keywords | set domain, methyltransferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29672.19 |
| Authors | Niwa, H.,Handa, N.,Takemoto, Y.,Ito, A.,Tomabechi, Y.,Umehara, T.,Shirouzu, M.,Yoshida, M.,Yokoyama, S. (deposition date: 2015-08-20, release date: 2016-04-27, Last modification date: 2024-10-23) |
| Primary citation | Takemoto, Y.,Ito, A.,Niwa, H.,Okamura, M.,Fujiwara, T.,Hirano, T.,Handa, N.,Umehara, T.,Sonoda, T.,Ogawa, K.,Tariq, M.,Nishino, N.,Dan, S.,Kagechika, H.,Yamori, T.,Yokoyama, S.,Yoshida, M. Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription J.Med.Chem., 59:3650-3660, 2016 Cited by PubMed Abstract: SET domain containing lysine methyltransferase 7/9 (Set7/9), a histone lysine methyltransferase (HMT), also methylates non-histone proteins including estrogen receptor (ER) α. ERα methylation by Set7/9 stabilizes ERα and activates its transcriptional activities, which are involved in the carcinogenesis of breast cancer. We identified cyproheptadine, a clinically approved antiallergy drug, as a Set7/9 inhibitor in a high-throughput screen using a fluorogenic substrate-based HMT assay. Kinetic and X-ray crystallographic analyses revealed that cyproheptadine binds in the substrate-binding pocket of Set7/9 and inhibits its enzymatic activity by competing with the methyl group acceptor. Treatment of human breast cancer cells (MCF7 cells) with cyproheptadine decreased the expression and transcriptional activity of ERα, thereby inhibiting estrogen-dependent cell growth. Our findings suggest that cyproheptadine can be repurposed for breast cancer treatment or used as a starting point for the discovery of an anti-hormone breast cancer drug through lead optimization. PubMed: 27088648DOI: 10.1021/acs.jmedchem.5b01732 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.005 Å) |
Structure validation
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