7SFF

Human DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA and Inhibitor GSK3852279B

7SFF の概要

• エントリーDOI: 10.2210/pdb7sff/pdb
• 分子名称: DNA (cytosine-5)-methyltransferase 1, DNA (12-MER), ZINC ION, ... (8 entities in total)
• 機能のキーワード: epigentics, dna methytransferase fold, maintenance methylation, inhibition, dna binding protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 107293.24

構造登録者

Horton, J.R.,Pathuri, S.,Cheng, X. (登録日: 2021-10-03, 公開日: 2022-03-30, 最終更新日: 2023-10-18)

主引用文献

Horton, J.R.,Pathuri, S.,Wong, K.,Ren, R.,Rueda, L.,Fosbenner, D.T.,Heerding, D.A.,McCabe, M.T.,Pappalardi, M.B.,Zhang, X.,King, B.W.,Cheng, X.
Structural characterization of dicyanopyridine containing DNMT1-selective, non-nucleoside inhibitors.
Structure, 30:793-802.e5, 2022

PubMed Abstract: DNMT1 maintains the parental DNA methylation pattern on newly replicated hemimethylated DNA. The failure of this maintenance process causes aberrant DNA methylation that affects transcription and contributes to the development and progression of cancers such as acute myeloid leukemia. Here, we structurally characterized a set of newly discovered DNMT1-selective, reversible, non-nucleoside inhibitors that bear a core 3,5-dicyanopyridine moiety, as exemplified by GSK3735967, to better understand their mechanism of inhibition. All of the dicyanopydridine-containing inhibitors examined intercalate into the hemimethylated DNA between two CpG base pairs through the DNA minor groove, resulting in conformational movement of the DNMT1 active-site loop. In addition, GSK3735967 introduces two new binding sites, where it interacts with and stabilizes the displaced DNMT1 active-site loop and it occupies an open aromatic cage in which trimethylated histone H4 lysine 20 is expected to bind. Our work represents a substantial step in generating potent, selective, and non-nucleoside inhibitors of DNMT1.

PubMed: 35395178
DOI: 10.1016/j.str.2022.03.009

実験手法

X-RAY DIFFRACTION (2.05 Å)