7X9D

DNMT3B in complex with harmine

7X9D の概要

• エントリーDOI: 10.2210/pdb7x9d/pdb
• 分子名称: DNA (cytosine-5)-methyltransferase 3B, DNA (cytosine-5)-methyltransferase 3-like, 7-METHOXY-1-METHYL-9H-BETA-CARBOLINE (3 entities in total)
• 機能のキーワード: inhibitor, comple, methyltransferase, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 113110.43

構造登録者

Cho, C.-C.,Yuan, H.S. (登録日: 2022-03-15, 公開日: 2023-03-15, 最終更新日: 2023-11-29)

主引用文献

Cho, C.C.,Lin, C.J.,Huang, H.H.,Yang, W.Z.,Fei, C.Y.,Lin, H.Y.,Lee, M.S.,Yuan, H.S.
Mechanistic Insights into Harmine-Mediated Inhibition of Human DNA Methyltransferases and Prostate Cancer Cell Growth.
Acs Chem.Biol., 18:1335-1350, 2023

PubMed Abstract: Mammalian DNA methyltransferases (DNMTs), including DNMT1, DNMT3A, and DNMT3B, are key DNA methylation enzymes and play important roles in gene expression regulation. Dysregulation of DNMTs is linked to various diseases and carcinogenesis, and therefore except for the two approved anticancer azanucleoside drugs, various non-nucleoside DNMT inhibitors have been identified and reported. However, the underlying mechanisms for the inhibitory activity of these non-nucleoside inhibitors still remain largely unknown. Here, we systematically tested and compared the inhibition activities of five non-nucleoside inhibitors toward the three human DNMTs. We found that harmine and nanaomycin A blocked the methyltransferase activity of DNMT3A and DNMT3B more efficiently than resveratrol, EGCG, and RG108. We further determined the crystal structure of harmine in complex with the catalytic domain of the DNMT3B-DNMT3L tetramer revealing that harmine binds at the adenine cavity of the SAM-binding pocket in DNMT3B. Our kinetics assays confirm that harmine competes with SAM to competitively inhibit DNMT3B-3L activity with a of 6.6 μM. Cell-based studies further show that harmine treatment inhibits castration-resistant prostate cancer cell (CRPC) proliferation with an IC of ∼14 μM. The CPRC cells treated with harmine resulted in reactivating silenced hypermethylated genes compared to the untreated cells, and harmine cooperated with an androgen antagonist, bicalutamide, to effectively inhibit the proliferation of CRPC cells. Our study thus reveals, for the first time, the inhibitory mechanism of harmine on DNMTs and highlights new strategies for developing novel DNMT inhibitors for cancer treatment.

PubMed: 37188336
DOI: 10.1021/acschembio.3c00065

実験手法

X-RAY DIFFRACTION (3.08 Å)