4WVL

Structure-Guided DOT1L Probe Optimization by Label-Free Ligand Displacement

4WVL の概要

• エントリーDOI: 10.2210/pdb4wvl/pdb
• 分子名称: Histone-lysine N-methyltransferase, H3 lysine-79 specific, N-[4-(acetylamino)butyl]-5'-[(3-{[(4-tert-butylphenyl)carbamoyl]amino}propyl)(propan-2-yl)amino]-5'-deoxyadenosine, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: dot1l, methyltransferase, inhibitor, leukemia, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 1
• 化学式量合計: 41539.08

構造登録者

Xu, X.,Dhe-Paganon, S.,Blacklow, S. (登録日: 2014-11-06, 公開日: 2014-12-03, 最終更新日: 2023-09-27)

主引用文献

Yi, J.S.,Federation, A.J.,Qi, J.,Dhe-Paganon, S.,Hadler, M.,Xu, X.,St Pierre, R.,Varca, A.C.,Wu, L.,Marineau, J.J.,Smith, W.B.,Souza, A.,Chory, E.J.,Armstrong, S.A.,Bradner, J.E.
Structure-Guided DOT1L Probe Optimization by Label-Free Ligand Displacement.
Acs Chem.Biol., 10:667-674, 2015

PubMed Abstract: The DOT1L lysine methyltransferase has emerged as a validated therapeutic target in MLL-rearranged (MLLr) acute leukemias. Although S-adenosylmethionine competitive inhibitors have demonstrated pharmacological proof-of-principle in MLLr-leukemia, these compounds require further optimization to improve cellular potency and pharmacokinetic stability. Limiting DOT1L inhibitor discovery and ligand optimization have been complex biochemical methods often using radionucleotides and cellular methods requiring prolonged culture. We therefore developed a new suite of assay technologies that allows comparative assessment of chemical tools for DOT1L in a miniaturized format. Coupling these assays with structural information, we developed new insights into DOT1L ligand binding and identified several functionalized probes with increased cellular potency (IC50 values ∼10 nM) and excellent selectivity for DOT1L. Together these assay technologies define a platform capability for discovery and optimization of small-molecule DOT1L inhibitors.

PubMed: 25397901
DOI: 10.1021/cb500796d

実験手法

X-RAY DIFFRACTION (2.41 Å)