3ess | pdb_00003ess
Catalytic fragment of Cholix toxin from Vibrio Cholerae in complex with the 1,8-Naphthalimide inhibitor
Structural highlights
FunctionCHXA_VIBCL An NAD-dependent ADP-ribosyltransferase (ADPRT), it catalyzes the transfer of the ADP-ribosyl moiety of oxidized NAD onto eukaryotic elongation factor 2 (eEF-2) thus arresting protein synthesis. It probably uses the eukaryotic prolow-density lipoprotein receptor-related protein 1 (LRP1) to enter mouse cells, although there seems to be at least one other receptor as well. Is active against mouse fibroblasts, Chinese hamster ovary eEF-2, brine shrimp (Artemia spp. nauplii) and upon expression in S.cerevisiae.[1] [2] Publication Abstract from PubMedThe 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. Yeast as a tool for characterizing mono-ADP-ribosyltransferase toxins.,Turgeon Z, White D, Jorgensen R, Visschedyk D, Fieldhouse RJ, Mangroo D, Merrill AR FEMS Microbiol Lett. 2009 Nov;300(1):97-106. Epub 2009 Aug 31. PMID:19793133[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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