5YX2

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

5YX2 の概要

• エントリーDOI: 10.2210/pdb5yx2/pdb
• 分子名称: DNA (cytosine-5)-methyltransferase 3A, DNA (cytosine-5)-methyltransferase 3-like, DNA (25-MER), ... (6 entities in total)
• 機能のキーワード: dnmt3a, dnmt3l, dna methylation, transferase-transferase regulator-dna complex, transferase/transferase regulator/dna
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : Q9Y6K1 Q9UJW3
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 130251.86

構造登録者

Zhang, Z.M.,Song, J. (登録日: 2017-12-01, 公開日: 2018-01-31, 最終更新日: 2025-09-17)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.653 Å)