Inhibition of the glucosyltransferase activity of clostridial Rho/Ras-glucosylating toxins by castanospermine.
Castanospermine was identified as an inhibitor of the Rho/Ras-glucosylating Clostridium sordellii lethal toxin and Clostridium difficile toxin B. Microinjection of castanospermine into embryonic bovine lung cells prevented the cytotoxic effects of toxins. The crystal structure of the glucosyltransferase domain of C. sordellii lethal toxin in complex with castanospermine, UDP and a calcium ion was solved at a resolution of 2.3A. The inhibitor binds in a conformation that brings its four hydroxyl groups and its N-atom almost exactly in the positions of the four hydroxyls and of the ring oxygen of the glucosyl moiety of UDP-glucose, respectively.
Jank
Thomas
T
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albertstrasse 25, Freiburg, Germany.
Ziegler
Mathias O P
MO
Schulz
Georg E
GE
Aktories
Klaus
K
D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D002417:Cattle; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007212:Indolizines / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054836:Indolizidines
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D005964:Glucosyltransferases; D007212:Indolizines; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; C072292:lethal toxin LT, Clostridium sordellii; C031815:toxB protein, Clostridium difficile; C037806:castanospermine; D054836:Indolizidines