8YHR

DHODH in complex with furocoumavirin

これはPDB形式変換不可エントリーです。

8YHR の概要

• エントリーDOI: 10.2210/pdb8yhr/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, OROTIC ACID, FLAVIN MONONUCLEOTIDE, ... (8 entities in total)
• 機能のキーワード: dihydroorotate dehydrogenase, dhodh, 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: 43690.29

構造登録者

Hara, K.,Okumura, H.,Nakahara, M.,Sato, M.,Hashimoto, H.,Osada, H.,Watanabe, K. (登録日: 2024-02-28, 公開日: 2024-05-22, 最終更新日: 2024-06-05)

主引用文献

Nakahara, M.,Watanabe, S.,Sato, M.,Okumura, H.,Kawatani, M.,Osada, H.,Hara, K.,Hashimoto, H.,Watanabe, K.
Structural and Functional Analyses of Inhibition of Human Dihydroorotate Dehydrogenase by Antiviral Furocoumavirin.
Biochemistry, 63:1241-1245, 2024

PubMed Abstract: Natural products are important sources of seed compounds for drug discovery. However, it has become difficult in recent years to discover new compounds with valuable pharmacological activities. On the other hand, among the vast number of natural products that have been isolated so far, a considerable number of compounds with specific biological activities are thought to be overlooked in screening that uses biological activity as an index. Therefore, it is conceivable that such overlooked useful compounds may be found by screening compound libraries that have been amassed previously through specific assays. Previously, NPD723, a member of the Natural Products Depository library comprised of a mixture of natural and non-natural products developed at RIKEN, and its metabolite H-006 were found to inhibit growth of various cancer cells at low nanomolar half-maximal inhibitory concentration. Subsequent analysis revealed that H-006 strongly inhibited human dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the pyrimidine biosynthetic pathway. Here, we elucidated the crystal structure of the DHODH-flavin mononucleotide-orotic acid-H-006 complex at 1.7 Å resolution to determine that furocoumavirin, the S-enantiomer of H-006, was the actual inhibitor. The overall mode of interaction of furocoumavirin with the inhibitor binding pocket was similar to that described for previously reported tight-binding inhibitors. However, the structural information together with kinetic characterizations of site-specific mutants identified key unique features that are considered to contribute to the sub-nanomolar inhibition of DHODH by furocoumavirin. Our finding identified new chemical features that could improve the design of human DHODH inhibitors.

PubMed: 38724483
DOI: 10.1021/acs.biochem.4c00120

実験手法

X-RAY DIFFRACTION (1.7 Å)