9LQ1

Structure of human DNMT3A-TCL1A complex

This is a non-PDB format compatible entry.

Summary for 9LQ1

• Entry DOI: 10.2210/pdb9lq1/pdb
• EMDB information: 63290
• Descriptor: Isoform 1 of DNA (cytosine-5)-methyltransferase 3A, T-cell leukemia/lymphoma protein 1A, ZINC ION (3 entities in total)
• Functional Keywords: complex, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 258289.56

Authors

Liu, Q.T.,Li, J.H. (deposition date: 2025-01-27, release date: 2025-11-05, Last modification date: 2026-04-15)

Primary citation

Liu, Q.,Li, J.,Wang, X.,Li, Y.,Wu, Y.,Han, Z.,Guo, Z.,Guo, L.,Wang, X.,Yuan, G.,Gao, Z.,Li, L.,Deng, D.
Molecular basis for the inhibition of de novo DNA methylation by TCL1A.
Nat Commun, 17:-, 2026

PubMed Abstract: DNA methyltransferases DNMT3A/B mediate de novo DNA methylation, essential for embryonic development and cell fate determination. Dysregulation of DNMT3A/B causes developmental defects and tumorigenesis. TCL1A is critical for embryogenesis but promotes lymphomagenesis when deregulated. Previous studies suggested TCL1A binds DNMT3A/B and inhibits their activity, but the mechanism remained unclear. Here, we report the cryo-EM structure of the DNMT3A-TCL1A complex, which comprises a DNMT3A dimer bound by two TCL1A dimers. TCL1A interacts with the catalytic domain of DNMT3A, overlapping with the DNMT3L-binding site, and induces extended conformational rearrangements. The target recognition domain and catalytic loop shift markedly, reducing DNA accessibility, while the catalytic loop occupies the SAM-binding pocket, thereby blocking methyltransferase activity. Supported by biochemical assays and molecular dynamics simulations, we propose a dynamic inhibition mechanism in which TCL1A exploits DNMT3A conformational plasticity to suppress de novo DNA methylation.

PubMed: 41786706
DOI: 10.1038/s41467-025-67710-8

Experimental method

ELECTRON MICROSCOPY (3.36 Å)