6MWY

The Prp8 intein of Cryptococcus gattii

6MWY の概要

• エントリーDOI: 10.2210/pdb6mwy/pdb
• 分子名称: Pre-mRNA-processing-splicing factor 8 (2 entities in total)
• 機能のキーワード: intein, fungus, cryptococcus gattii, hydrolase
• 由来する生物種: Cryptococcus gattii serotype B (Filobasidiella gattii)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 73341.92

構造登録者

Li, Z.,Fu, B.,Green, C.M.,Lang, Y.,Zhang, J.,Oven, T.S.,Li, X.,Callahan, B.P.,Chaturvedi, S.,Belfort, M.,Liao, G.,Li, H. (登録日: 2018-10-30, 公開日: 2019-11-06, 最終更新日: 2024-10-23)

主引用文献

Li, Z.,Fu, B.,Green, C.M.,Liu, B.,Zhang, J.,Lang, Y.,Chaturvedi, S.,Belfort, M.,Liao, G.,Li, H.
Cisplatin protects mice from challenge ofCryptococcus neoformansby targeting the Prp8 intein.
Emerg Microbes Infect, 8:895-908, 2019

PubMed Abstract: The Prp8 intein is one of the most widespread eukaryotic inteins, present in important pathogenic fungi, including and species. Because the processed Prp8 carries out essential and non-redundant cellular functions, a Prp8 intein inhibitor is a mechanistically novel antifungal agent. In this report, we demonstrated that cisplatin, an FDA-approved cancer drug, significantly arrested growth of Prp8 intein-containing fungi but only poorly inhibited growth of intein-free species. These results suggest that cisplatin arrests fungal growth through specific inhibition of the Prp8 intein. Cisplatin was also found to significantly inhibit growth of in a mouse model. Our results further showed that cisplatin inhibited Prp8 intein splicing in a dose-dependent manner by direct binding to the Prp8 intein. Crystal structures of the apo- and cisplatin-bound Prp8 inteins revealed that two degenerate cisplatin molecules bind at the intein active site. Mutation of the splicing-site residues led to loss of cisplatin binding, as well as impairment of intein splicing. Finally, we found that overexpression of the Prp8 intein in cryptococcal species conferred cisplatin resistance. Overall, these results indicate that the Prp8 intein is a novel antifungal target worth further investigation.

PubMed: 31223062
DOI: 10.1080/22221751.2019.1625727

実験手法

X-RAY DIFFRACTION (2.594 Å)