8XEE

Human DNMT3B mutant-R823G

8XEE の概要

• エントリーDOI: 10.2210/pdb8xee/pdb
• 分子名称: DNA (cytosine-5)-methyltransferase 3B, DNA (cytosine-5)-methyltransferase 3-like, S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• 機能のキーワード: methyltransferase, dna methylation, dna binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 112864.08

構造登録者

Cho, C.-C.,Yuan, H.S. (登録日: 2023-12-11, 公開日: 2024-10-23)

主引用文献

Cho, C.C.,Fei, C.Y.,Jiang, B.C.,Yang, W.Z.,Yuan, H.S.
Molecular mechanisms for DNA methylation defects induced by ICF syndrome-linked mutations in DNMT3B.
Protein Sci., 33:e5131-e5131, 2024

PubMed Abstract: DNA methyltransferase 3B (DNMT3B) plays a crucial role in DNA methylation during mammalian development. Mutations in DNMT3B are associated with human genetic diseases, particularly immunodeficiency, centromere instability, facial anomalies (ICF) syndrome. Although ICF syndrome-related missense mutations in the DNMT3B have been identified, their precise impact on protein structure and function remains inadequately explored. Here, we delve into the impact of four ICF syndrome-linked mutations situated in the DNMT3B dimeric interface (H814R, D817G, V818M, and R823G), revealing that each of these mutations compromises DNA-binding and methyltransferase activities to varying degrees. We further show that H814R, D817G, and V818M mutations severely disrupt the proper assembly of DNMT3B homodimer, whereas R823G does not. We also determined the first crystal structure of the methyltransferase domain of DNMT3B-DNMT3L tetrameric complex hosting the R823G mutation showing that the R823G mutant displays diminished hydrogen bonding interactions around T775, K777, G823, and Q827 in the protein-DNA interface, resulting in reduced DNA-binding affinity and a shift in sequence preference of +1 to +3 flanking positions. Altogether, our study uncovers a wide array of fundamental defects triggered by DNMT3B mutations, including the disassembly of DNMT3B dimers, reduced DNA-binding capacity, and alterations in flanking sequence preferences, leading to aberrant DNA hypomethylation and ICF syndrome.

PubMed: 39290110
DOI: 10.1002/pro.5131

実験手法

X-RAY DIFFRACTION (3.03 Å)