3ESS

Catalytic fragment of Cholix toxin from Vibrio Cholerae in complex with the 1,8-Naphthalimide inhibitor

3ESS の概要

• エントリーDOI: 10.2210/pdb3ess/pdb
• 関連するPDBエントリー: 2q5t 2q6m
• 分子名称: Cholix toxin, 1H-benzo[de]isoquinoline-1,3(2H)-dione (3 entities in total)
• 機能のキーワード: adp-ribosyl transferase, domain iii (c-terminal catalytic domain), alpha-beta complex, toxin, transferase
• 由来する生物種: Vibrio cholerae
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25749.38

構造登録者

Merrill, A.R.,Jorgensen, R. (登録日: 2008-10-06, 公開日: 2009-09-15, 最終更新日: 2023-09-06)

主引用文献

Turgeon, Z.,White, D.,Jorgensen, R.,Visschedyk, D.,Fieldhouse, R.J.,Mangroo, D.,Merrill, A.R.
Yeast as a tool for characterizing mono-ADP-ribosyltransferase toxins
Fems Microbiol.Lett., 300:97-106, 2009

PubMed Abstract: The emergence of bacterial antibiotic resistance poses a significant challenge in the pursuit of novel therapeutics, making new strategies for drug discovery imperative. We have developed a yeast growth-defect phenotypic screen to help solve this current dilemma. This approach facilitates the identification and characterization of a new diphtheria toxin (DT) group, ADP-ribosyltransferase toxins from pathogenic bacteria. In addition, this assay utilizes Saccharomyces cerevisiae, a reliable model for bacterial toxin expression, to streamline the identification and characterization of new inhibitors against this group of bacterial toxins that may be useful for antimicrobial therapies. We show that a mutant of the elongation factor 2 target protein in yeast, G701R, confers resistance to all DT group toxins and recovers the growth-defect phenotype in yeast. We also demonstrate the ability of a potent small-molecule toxin inhibitor, 1,8-naphthalimide (NAP), to alleviate the growth defect caused by toxin expression in yeast. Moreover, we determined the crystal structure of the NAP inhibitor-toxin complex at near-atomic resolution to provide insight into the inhibitory mechanism. Finally, the NAP inhibitor shows therapeutic protective effects against toxin invasion of mammalian cells, including human lung cells.

PubMed: 19793133
DOI: 10.1111/j.1574-6968.2009.01777.x

実験手法

X-RAY DIFFRACTION (1.191 Å)