9MPP
The cryo-EM structure of nucleosome-bound DNA methyltransferases DNMT3A2 and DNMT3L
Summary for 9MPP
| Entry DOI | 10.2210/pdb9mpp/pdb |
| Related | 9MP0 9MPO |
| EMDB information | 48494 48495 48496 48497 48498 |
| Descriptor | Histone H3.2, S-ADENOSYL-L-HOMOCYSTEINE, Histone H4, ... (10 entities in total) |
| Functional Keywords | methyltransferase, dnmt-nucleosome complex, transferase, transferase-dna complex, dna binding protein |
| Biological source | Xenopus laevis (African clawed frog) More |
| Total number of polymer chains | 14 |
| Total formula weight | 455838.66 |
| Authors | Yan, Y.,Zhou, X.E.,Xu, T.H. (deposition date: 2024-12-31, release date: 2025-10-08, Last modification date: 2025-11-19) |
| Primary citation | Yan, Y.,Zhou, X.E.,Thomas, S.L.,Liu, M.,Lai, G.Q.,Worden, E.J.,Jones, P.A.,Xu, T.H. Mechanisms of DNMT3A-3L-mediated de novo DNA methylation on chromatin. Nat.Struct.Mol.Biol., 2025 Cited by PubMed Abstract: De novo DNA methylation is mediated by DNA methyltransferases DNMT3A and DNMT3B, in cooperation with the catalytically inactive paralogs DNMT3L and DNMT3B3. DNMT3L is predominantly expressed in embryonic stem cells to establish methylation patterns and is silenced upon differentiation, with DNMT3B3 substituting in somatic cells. Here we present high-resolution cryo-electron microscopy structures of nucleosome-bound, full-length DNMT3A2-3L and its oligomeric assemblies in the nucleosome-free state. We identified the critical role of DNMT3L as a histone modification sensor, guiding chromatin engagement through a mechanism distinct from DNMT3B3. The structures show a 180° rotated 'switching helix' in DNMT3L that prevents direct interaction with the nucleosome acidic patch. Instead, nucleosome binding is mediated by the DNMT3L ADD domain, while the DNMT3A PWWP domain exhibits reduced engagement in the absence of H3K36 methylation. The oligomeric arrangement of DNMT3A2-3L in nucleosome-free states highlights its dynamic assembly and potential allosteric regulation. We further capture dynamic structural movements of DNMT3A2-3L on nucleosomes. These findings uncover a previously unknown mechanism by which DNMT3A-3L mediates de novo DNA methylation on chromatin through complex assembly, histone tail sensing, dynamic DNA search and regulated nucleosome engagement, providing insights into epigenetic regulation. PubMed: 41174279DOI: 10.1038/s41594-025-01704-4 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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