7E8D

NSD2 E1099K mutant bound to nucleosome

7E8D の概要

• エントリーDOI: 10.2210/pdb7e8d/pdb
• EMDBエントリー: 31015
• 分子名称: Histone H3.1, Histone H4, Histone H2A type 1, ... (9 entities in total)
• 機能のキーワード: chromatin, epigenetics, histone methyltransferase, muitiple myeloma, gene regulation
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 11
• 化学式量合計: 252528.67

構造登録者

Sengoku, T.,Sato, K.,Nishizawa, T.,Nureki, O.,Ogata, K. (登録日: 2021-03-01, 公開日: 2021-11-10, 最終更新日: 2025-06-18)

主引用文献

Sato, K.,Kumar, A.,Hamada, K.,Okada, C.,Oguni, A.,Machiyama, A.,Sakuraba, S.,Nishizawa, T.,Nureki, O.,Kono, H.,Ogata, K.,Sengoku, T.
Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2.
Nat Commun, 12:6605-6605, 2021

PubMed Abstract: Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide the development of specific inhibitors of NSD2.

PubMed: 34782608
DOI: 10.1038/s41467-021-26913-5

実験手法

ELECTRON MICROSCOPY (2.8 Å)