5MVS

Crystal structure of Dot1L in complex with adenosine and inhibitor CPD1 [N6-(2,6-dichlorophenyl)-N6-(pent-2-yn-1-yl)quinoline-4,6-diamine]

5MVS の概要

• エントリーDOI: 10.2210/pdb5mvs/pdb
• 分子名称: Histone-lysine N-methyltransferase, H3 lysine-79 specific, ADENOSINE, N~6~-(2,6-dichlorophenyl)-N~6~-(pent-2-yn-1-yl)quinoline-4,6-diamine, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, methyltransferase, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q8TEK3
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78338.31

構造登録者

Be, C.,Koch, E.,Gaul, C.,Stauffer, F.,Moebitz, H.,Scheufler, C. (登録日: 2017-01-17, 公開日: 2017-03-22, 最終更新日: 2024-01-17)

主引用文献

Mobitz, H.,Machauer, R.,Holzer, P.,Vaupel, A.,Stauffer, F.,Ragot, C.,Caravatti, G.,Scheufler, C.,Fernandez, C.,Hommel, U.,Tiedt, R.,Beyer, K.S.,Chen, C.,Zhu, H.,Gaul, C.
Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.
ACS Med Chem Lett, 8:338-343, 2017

PubMed Abstract: Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of , a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of and , an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of , a highly potent, selective and structurally novel Dot1L inhibitor.

PubMed: 28337327
DOI: 10.1021/acsmedchemlett.6b00519

実験手法

X-RAY DIFFRACTION (2.18 Å)