11OI

Cryo-EM structure of human DNMT3A homo-hexamer

Summary for 11OI

• Entry DOI: 10.2210/pdb11oi/pdb
• EMDB information: 75886
• Descriptor: DNA (cytosine-5)-methyltransferase 3A, S-ADENOSYL-L-HOMOCYSTEINE, ZINC ION (3 entities in total)
• Functional Keywords: dna (cytosine-5)-methyltransferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 436109.33

Authors

Song, J.,Lu, J.,Chen, J. (deposition date: 2026-03-06, release date: 2026-08-19, Last modification date: 2026-09-02)

Primary citation

Chen, J.,Lu, J.,Long, Z.,Yoon, S.,Fukunaga, M.,Song, J.
Multidomain interaction governs the filamentous assembly of the dominant-negative DNMT3A R882H mutant.
Proc.Natl.Acad.Sci.USA, 123:e2609226123-e2609226123, 2026

PubMed Abstract: DNA methyltransferase DNMT3A-mediated de novo DNA methylation is important for proper regulation of gene expression and genomic stability in development. The DNMT3A R882H (DNMT3A) mutation, a hot-spot mutation in acute myeloid leukemia and developmental disorders, exerts a dominant-negative effect in DNMT3A-mediated DNA methylation through promoting high-order protein assembly. However, due to the lack of structural knowledge on DNMT3A homo-oligomers, the mechanism behind wild-type DNMT3A (DNMT3A) and DNMT3A polymerization remains unclear. Here, we report the single-particle cryo-EM structures of homo-oligomeric DNMT3A and filamentous DNMT3A, revealing the role of the regulatory Pro-Trp-Trp-Pro (PWWP) and ATRX-DNMT3-DNMT3L (ADD) domains of DNMT3A in their dynamic assembly. While the oligomeric assembly of DNMT3A is mainly driven by the well-characterized oligomer interfaces in the methyltransferase domain, the autoinhibitory interaction of the PWWP and ADD domains in DNMT3A places them in a position for intermolecular contact, thereby contributing to the filamentous assembly of DNMT3A. Disrupting the autoinhibitory interaction facilitates the transition of DNMT3A polymer toward the low-order oligomeric assembly, reinforcing the aggregation-attenuation effect of the previously characterized oligomer-interface mutation R676K. Together, this study uncovers a multidomain cooperated assembly mechanism for DNMT3A, with important implication in development of effective therapeutic strategies against DNMT3A-associated diseases.

PubMed: 42640801
DOI: 10.1073/pnas.2609226123

Experimental method

ELECTRON MICROSCOPY (3.66 Å)