Inhibition of the glucosyltransferase activity of clostridial Rho/Ras-glucosylating toxins by castanospermine

FEBS Lett. 2008 Jun 25;582(15):2277-82. doi: 10.1016/j.febslet.2008.05.025. Epub 2008 May 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Toxins / antagonists & inhibitors*
  • Bacterial Toxins / chemistry
  • Catalytic Domain
  • Cattle
  • Cells, Cultured
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glucosyltransferases / antagonists & inhibitors*
  • Glucosyltransferases / chemistry
  • Indolizines / chemistry
  • Indolizines / pharmacology*
  • Protein Conformation
  • ras Proteins / metabolism
  • rho GTP-Binding Proteins / metabolism

Substances

  • Bacterial Proteins
  • Bacterial Toxins
  • Enzyme Inhibitors
  • Indolizines
  • lethal toxin LT, Clostridium sordellii
  • toxB protein, Clostridium difficile
  • Glucosyltransferases
  • ras Proteins
  • rho GTP-Binding Proteins
  • castanospermine