6OC0

Crystal structure of human DHODH with OSU-03012

6OC0 の概要

• エントリーDOI: 10.2210/pdb6oc0/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, OROTIC ACID, FLAVIN MONONUCLEOTIDE, ... (6 entities in total)
• 機能のキーワード: dhodh, inhibitor, osu-03012, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41486.96

構造登録者

Durst, M.A.,Lavie, A. (登録日: 2019-03-21, 公開日: 2019-11-13, 最終更新日: 2023-10-11)

主引用文献

Abt, E.R.,Rosser, E.W.,Durst, M.A.,Lok, V.,Poddar, S.,Le, T.M.,Cho, A.,Kim, W.,Wei, L.,Song, J.,Capri, J.R.,Xu, S.,Wu, N.,Slavik, R.,Jung, M.E.,Damoiseaux, R.,Czernin, J.,Donahue, T.R.,Lavie, A.,Radu, C.G.
Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.
Cell Chem Biol, 27:197-, 2020

PubMed Abstract: Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity. The JNK inhibitor JNK-IN-8 was found to potently inhibit nucleoside transport and engage ENT1. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant de novo pathway enzyme DHODH and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH.

PubMed: 31734178
DOI: 10.1016/j.chembiol.2019.10.012

実験手法

X-RAY DIFFRACTION (1.4 Å)