7SFC

Human DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA and Inhibitor GSK3735967A

Summary for 7SFC

• Entry DOI: 10.2210/pdb7sfc/pdb
• Descriptor: DNA (cytosine-5)-methyltransferase 1, DNA (12-MER), ZINC ION, ... (8 entities in total)
• Functional Keywords: epigentics, dna methytransferase fold, maintenance methylation, inhibition, dna binding protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 108982.41

Authors

Horton, J.R.,Pathuri, S.,Cheng, X. (deposition date: 2021-10-03, release date: 2022-03-30, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.97 Å)