6F57

Crystal structure of DNMT3A-DNMT3L in complex with single CpG-containing DNA

Summary for 6F57

• Entry DOI: 10.2210/pdb6f57/pdb
• Descriptor: DNA (cytosine-5)-methyltransferase 3A, DNA (cytosine-5)-methyltransferase 3-like, DNA (5'-D(*AP*GP*AP*GP*CP*GP*CP*AP*TP*G)-3'), ... (5 entities in total)
• Functional Keywords: dnmt3a, dnmt3l, dna methylation, dna binding protein, transferase-dna complex, transferase/dna
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q9Y6K1 Q9UJW3
• Total number of polymer chains: 8
• Total formula weight: 127256.02

Authors

Zhang, Z.M.,Song, J. (deposition date: 2017-12-01, release date: 2018-01-31, Last modification date: 2024-10-23)

Primary citation

Zhang, Z.M.,Lu, R.,Wang, P.,Yu, Y.,Chen, D.,Gao, L.,Liu, S.,Ji, D.,Rothbart, S.B.,Wang, Y.,Wang, G.G.,Song, J.
Structural basis for DNMT3A-mediated de novo DNA methylation.
Nature, 554:387-391, 2018

PubMed Abstract: DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-ångström crystal structure of the DNMT3A-DNMT3L-DNA complex in which two DNMT3A monomers simultaneously attack two cytosine-phosphate-guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.

PubMed: 29414941
DOI: 10.1038/nature25477

Experimental method

X-RAY DIFFRACTION (3.098 Å)