7CA1

Crystal structure of dihydroorotase in complex with plumbagin from Saccharomyces cerevisiae

Summary for 7CA1

• Entry DOI: 10.2210/pdb7ca1/pdb
• Related: 6L0A 6L0B
• Descriptor: Dihydroorotase, (2S)-2-hydroxybutanedioic acid, ZINC ION, ... (4 entities in total)
• Functional Keywords: dihydropyrimidinase, dihydroorotase, metalloenzyme, hydrolase
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
• Total number of polymer chains: 4
• Total formula weight: 167081.22

Authors

Guan, H.H.,Huang, Y.H.,Huang, C.Y.,Chen, C.J. (deposition date: 2020-06-08, release date: 2021-06-09, Last modification date: 2023-11-29)

Primary citation

Guan, H.H.,Huang, Y.H.,Lin, E.S.,Chen, C.J.,Huang, C.Y.
Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis.
Int J Mol Sci, 22:-, 2021

PubMed Abstract: Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway for pyrimidine nucleotides, and an attractive target for potential anticancer chemotherapy. By screening plant extracts and performing GC-MS analysis, we identified and characterized that the potent anticancer drug plumbagin (PLU), isolated from the carnivorous plant , was a competitive inhibitor of DHOase. We also solved the complexed crystal structure of yeast DHOase with PLU (PDB entry 7CA1), to determine the binding interactions and investigate the binding modes. Mutational and structural analyses indicated the binding of PLU to DHOase through loop-in mode, and this dynamic loop may serve as a drug target. PLU exhibited cytotoxicity on the survival, migration, and proliferation of 4T1 cells and induced apoptosis. These results provide structural insights that may facilitate the development of new inhibitors targeting DHOase, for further clinical anticancer chemotherapies.

PubMed: 34202294
DOI: 10.3390/ijms22136861

Experimental method

X-RAY DIFFRACTION (3.6 Å)