7V0E

Crystal structure of the macro-oligomeric form of DNMT3B methyltransferase domain.

Summary for 7V0E

• Entry DOI: 10.2210/pdb7v0e/pdb
• Descriptor: DNA (cytosine-5)-methyltransferase 3B, S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• Functional Keywords: dnmt3b, dna methylation, methyltransferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 263328.29

Authors

Gao, L.,Lu, J.,Song, J. (deposition date: 2022-05-10, release date: 2022-06-22, Last modification date: 2023-10-18)

Primary citation

Gao, L.,Guo, Y.,Biswal, M.,Lu, J.,Yin, J.,Fang, J.,Chen, X.,Shao, Z.,Huang, M.,Wang, Y.,Wang, G.G.,Song, J.
Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations.
Nat Commun, 13:4249-4249, 2022

PubMed Abstract: DNA methyltransferase DNMT3B plays an essential role in establishment of DNA methylation during embryogenesis. Mutations of DNMT3B are associated with human diseases, notably the immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome. How ICF mutations affect DNMT3B activity is not fully understood. Here we report the homo-oligomeric structure of DNMT3B methyltransferase domain, providing insight into DNMT3B-mediated DNA methylation in embryonic stem cells where the functional regulator DNMT3L is dispensable. The interplay between one of the oligomer interfaces (FF interface) and the catalytic loop renders DNMT3B homo-oligomer a conformation and activity distinct from the DNMT3B-DNMT3L heterotetramer, and a greater vulnerability to certain ICF mutations. Biochemical and cellular analyses further reveal that the ICF mutations of FF interface impair the DNA binding and heterochromatin targeting of DNMT3B, leading to reduced DNA methylation in cells. Together, this study provides a mechanistic understanding of DNMT3B-mediated DNA methylation and its dysregulation in disease.

PubMed: 35869095
DOI: 10.1038/s41467-022-31933-w

Experimental method

X-RAY DIFFRACTION (3.27016388184 Å)