3SR4

Crystal Structure of Human DOT1L in Complex with a Selective Inhibitor

3SR4 の概要

• エントリーDOI: 10.2210/pdb3sr4/pdb
• 関連するPDBエントリー: 1NW3 3QOW 3QOX
• 分子名称: Histone-lysine N-methyltransferase, H3 lysine-79 specific, (2S)-2-azanyl-4-[[(2S,3S,4R,5R)-5-[6-(methylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methylsulfanyl]butanoic acid, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: hdot1, histone lysine methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (Probable): Q8TEK3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41396.86

構造登録者

Diao, J.,Chen, P.,Yao, Y.,Prasad, B.V.V.,Song, Y. (登録日: 2011-07-06, 公開日: 2011-10-05, 最終更新日: 2023-09-13)

主引用文献

Yao, Y.,Chen, P.,Diao, J.,Cheng, G.,Deng, L.,Anglin, J.L.,Prasad, B.V.,Song, Y.
Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis, and Crystallographic Studies.
J.Am.Chem.Soc., 133:16746-16749, 2011

PubMed Abstract: Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC(50) values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The X-ray crystal structure of a DOT1L-inhibitor complex reveals that the N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.

PubMed: 21936531
DOI: 10.1021/ja206312b

実験手法

X-RAY DIFFRACTION (2.5 Å)