6L0B

Crystal structure of dihydroorotase in complex with fluorouracil from Saccharomyces cerevisiae

6L0B の概要

• エントリーDOI: 10.2210/pdb6l0b/pdb
• 関連するPDBエントリー: 6L0A
• 分子名称: Dihydroorotase, ZINC ION, 5-FLUOROURACIL, ... (4 entities in total)
• 機能のキーワード: dihydropyrimidinase, dihydroorotase, metalloenzyme, hydrolase
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 166957.00

構造登録者

Guan, H.H.,Huang, Y.H.,Huang, C.Y.,Chen, C.J. (登録日: 2019-09-26, 公開日: 2020-12-02, 最終更新日: 2023-11-22)

主引用文献

Guan, H.H.,Huang, Y.H.,Lin, E.S.,Chen, C.J.,Huang, C.Y.
Structural basis for the interaction modes of dihydroorotase with the anticancer drugs 5-fluorouracil and 5-aminouracil.
Biochem.Biophys.Res.Commun., 551:33-37, 2021

PubMed Abstract: Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway of pyrimidine nucleotides and considered an attractive target for potential antimalarial, anticancer, and antipathogen chemotherapy. Whether the FDA-approved clinical drug 5-fluorouracil (5-FU) that is used to target the enzyme thymidylate synthase for anticancer therapy can also bind to DHOase remains unknown. Here, we report the crystal structures of DHOase from Saccharomyces cerevisiae (ScDHOase) complexed with malate, 5-FU, and 5-aminouracil (5-AU). ScDHOase shares structural similarity with Escherichia coli DHOase. We also characterized the binding of 5-FU and 5-AU to ScDHOase by using the fluorescence quenching method. These complexed structures revealed that residues Arg18, Asn43, Thr106, and Ala275 of ScDHOase were involved in the 5-FU (PDB entry 6L0B) and 5-AU binding (PDB entry 6L0F). Overall, these results provide structural insights that may facilitate the development of new inhibitors targeting DHOase and constitute the 5-FU and 5-AU interactomes for further clinical chemotherapies.

PubMed: 33714757
DOI: 10.1016/j.bbrc.2021.03.001

実験手法

X-RAY DIFFRACTION (2.7 Å)