5DTM

Crystal structure of Dot1L in complex with inhibitor CPD1 [4-(2,6-dichlorobenzoyl)-N-methyl-1H-pyrrole-2-carboxamide]

5DTM の概要

• エントリーDOI: 10.2210/pdb5dtm/pdb
• 分子名称: Histone-lysine N-methyltransferase, H3 lysine-79 specific, 4-(2,6-dichlorobenzoyl)-N-methyl-1H-pyrrole-2-carboxamide (3 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: 77507.46

構造登録者

Scheufler, C.,Be, C.,Moebitz, H.,Stauffer, F. (登録日: 2015-09-18, 公開日: 2016-06-15, 最終更新日: 2024-01-10)

主引用文献

Scheufler, C.,Mobitz, H.,Gaul, C.,Ragot, C.,Be, C.,Fernandez, C.,Beyer, K.S.,Tiedt, R.,Stauffer, F.
Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.
Acs Med.Chem.Lett., 7:730-734, 2016

PubMed Abstract: Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was cocrystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting within the SAM binding pocket but induces a pocket adjacent to the SAM binding site.

PubMed: 27563394
DOI: 10.1021/acsmedchemlett.6b00168

実験手法

X-RAY DIFFRACTION (2.2 Å)