3ESS

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

Summary for 3ESS

• Entry DOI: 10.2210/pdb3ess/pdb
• Related: 2q5t 2q6m
• Descriptor: Cholix toxin, 1H-benzo[de]isoquinoline-1,3(2H)-dione (3 entities in total)
• Functional Keywords: adp-ribosyl transferase, domain iii (c-terminal catalytic domain), alpha-beta complex, toxin, transferase
• Biological source: Vibrio cholerae
• Total number of polymer chains: 1
• Total formula weight: 25749.38

Authors

Merrill, A.R.,Jorgensen, R. (deposition date: 2008-10-06, release date: 2009-09-15, Last modification date: 2023-09-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.191 Å)