5YLT

Crystal structure of SET7/9 in complex with a cyproheptadine derivative

Summary for 5YLT

• Entry DOI: 10.2210/pdb5ylt/pdb
• Descriptor: Histone-lysine N-methyltransferase SETD7, SINEFUNGIN, 2-(1-methylpiperidin-4-ylidene)tricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-6-ol, ... (5 entities in total)
• Functional Keywords: set domain, methyltransferase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 30044.31

Authors

Hirano, T.,Fujiwara, T.,Niwa, H.,Hirano, M.,Ohira, K.,Okazaki, Y.,Sato, S.,Umehara, T.,Maemoto, Y.,Ito, A.,Yoshida, M.,Kagechika, H. (deposition date: 2017-10-19, release date: 2018-06-20, Last modification date: 2024-10-16)

Primary citation

Hirano, T.,Fujiwara, T.,Niwa, H.,Hirano, M.,Ohira, K.,Okazaki, Y.,Sato, S.,Umehara, T.,Maemoto, Y.,Ito, A.,Yoshida, M.,Kagechika, H.
Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine.
ChemMedChem, 13:1530-1540, 2018

PubMed Abstract: The histone methyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2-hydroxy group showed the most potent activity. On the other hand, a 3-hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2-hydroxycyproheptadine. These results are expected to be helpful for further structure-based development of SET7/9 inhibitors.

PubMed: 29882380
DOI: 10.1002/cmdc.201800233

Experimental method

X-RAY DIFFRACTION (1.69 Å)