9V5P

Human DNMT1 (aa 698-1616) in complex with hemimethylated dsDNA and inhibitor DMT207

This is a non-PDB format compatible entry.

Summary for 9V5P

• Entry DOI: 10.2210/pdb9v5p/pdb
• EMDB information: 64791
• Descriptor: DNA (cytosine-5)-methyltransferase 1, DNA (5'-D(*CP*CP*TP*TP*CP*CP*GP*TP*AP*AP*GP*T)-3'), DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3'), ... (6 entities in total)
• Functional Keywords: dna methyltransferas 1, inhibitor, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 112269.86

Authors

Li, Z. (deposition date: 2025-05-26, release date: 2026-04-08)

Primary citation

Shen, Y.,Wei, J.,Tang, S.,Wu, D.,Zong, L.,Ma, S.,Xiong, Q.,Gong, R.,Xu, S.,Peng, C.,Feng, Q.,Liu, S.,Liu, Q.,Ye, Y.,Zhao, Q.,Luo, C.,Huang, P.,Li, Z.,Kong, X.,Lan, X.
Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating beta-Thalassemia.
Adv Sci, 13:e13469-e13469, 2026

PubMed Abstract: β-thalassemia is a recessively inherited blood disorder affecting millions worldwide. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy, yet existing DNA methyltransferase (DNMT) inhibitors, although effective HbF inducers, currently are not approved for β-thalassemia treatment. Here, we report that DMT207, a novel non-nucleoside DNMT1 inhibitor, robustly reactivates HbF in HUDEP-2 cells and adult primary erythroblasts with minimal toxicity. In a mouse model of β-thalassemia, DMT207 effectively elevates the levels of mouse fetal- and embryonic-type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly. Further multi-omics analyses expose γ-globin as one of the most sensitive genes with promoter demethylation and transcriptional activation following DMT207 treatment. Mechanistically, DMT207 traps DNMT1 into a catalytically inactive conformation and concurrently enhances its interaction with UHRF1, which partially contributes to DNMT1 degradation. These findings highlight the therapeutic potential of DMT207 for β-thalassemia and support its further preclinical development.

PubMed: 41347631
DOI: 10.1002/advs.202513469

Experimental method

ELECTRON MICROSCOPY (2.85 Å)