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PDBsum entry 3ess
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Transferase,toxin
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PDB id
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3ess
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References listed in PDB file
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Key reference
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Title
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Yeast as a tool for characterizing mono-Adp-Ribosyltransferase toxins.
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Authors
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Z.Turgeon,
D.White,
R.Jørgensen,
D.Visschedyk,
R.J.Fieldhouse,
D.Mangroo,
A.R.Merrill.
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Ref.
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Fems Microbiol Lett, 2009,
300,
97.
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PubMed id
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Abstract
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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.
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