6OC1

Crystal structure of human DHODH with TAK-632

Summary for 6OC1

• Entry DOI: 10.2210/pdb6oc1/pdb
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, OROTIC ACID, FLAVIN MONONUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: dhodh, inhibitor, tak-632, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 41387.80

Authors

Durst, M.A.,Lavie, A. (deposition date: 2019-03-21, release date: 2019-11-13, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)