7E3U

Crystal structure of the Pseudomonas aeruginosa dihydropyrimidinase complexed with 5-AU

7E3U の概要

• エントリーDOI: 10.2210/pdb7e3u/pdb
• 分子名称: D-hydantoinase/dihydropyrimidinase, 5-AMINO-1H-PYRIMIDINE-2,4-DIONE, ZINC ION, ... (4 entities in total)
• 機能のキーワード: hydrolase, dihydropyrimidinase
• 由来する生物種: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 105020.42

構造登録者

Yang, Y.C.,Luo, R.H.,Huang, Y.H.,Huang, C.Y.,Lin, E.S. (登録日: 2021-02-09, 公開日: 2022-02-16, 最終更新日: 2023-11-29)

主引用文献

Lin, E.S.,Luo, R.H.,Yang, Y.C.,Huang, C.Y.
Molecular Insights into How the Dimetal Center in Dihydropyrimidinase Can Bind the Thymine Antagonist 5-Aminouracil: A Different Binding Mode from the Anticancer Drug 5-Fluorouracil.
Bioinorg Chem Appl, 2022:1817745-1817745, 2022

PubMed Abstract: Dihydropyrimidinase (DHPase) is a key enzyme for pyrimidine degradation. DHPase contains a binuclear metal center in which two Zn ions are bridged by a posttranslationally carbamylated lysine. DHPase catalyzes the hydrolysis of dihydrouracil to -carbamoyl--alanine. Whether 5-aminouracil (5-AU), a thymine antagonist and an anticancer drug that can block DNA synthesis and induce replication stress, can interact with DHPase remains to be investigated. In this study, we determined the crystal structure of DHPase (PaDHPase) complexed with 5-AU at 2.1 Å resolution (PDB entry 7E3U). This complexed structure revealed that 5-AU interacts with Zn (3.2 Å), Zn (3.0 Å), the main chains of residues Ser289 (2.8 Å) and Asn337 (3.3 Å), and the side chain of residue Tyr155 (2.8 Å). These residues are also known as the substrate-binding sites of DHPase. Dynamic loop I (amino acid residues Pro65-Val70) in PaDHPase is not involved in the binding of 5-AU. The fluorescence quenching analysis and site-directed mutagenesis were used to confirm the binding mode revealed by the complexed crystal structure. The 5-AU binding mode of PaDHPase is, however, different from that of 5-fluorouracil, the best-known fluoropyrimidine used for anticancer therapy. These results provide molecular insights that may facilitate the development of new inhibitors targeting DHPase and constitute the 5-AU interactome.

PubMed: 35198016
DOI: 10.1155/2022/1817745

実験手法

X-RAY DIFFRACTION (2.159 Å)