Clostridioides difficile toxin B N-terminal glucosyltransferase domain (TcdB-GTD)

The Clostridioides difficile toxin B N-terminal glucosyltransferase domain (TcdB-GTD) is the primary cytotoxic component of the TcdB protein, a major virulence factor in C. difficile infection (UniProt P18177). Upon translocation into the host cell cytosol, the GTD is released via autoproteolysis and catalyzes the transfer of glucose from UDP-glucose to Rho family GTPases (PMID: 29305546). This covalent modification inactivates Rho, Rac, and Cdc42, leading to actin cytoskeleton disassembly and loss of intestinal epithelial barrier integrity (PMID: 22307132). Clinically, this damage results in the symptoms of pseudomembranous colitis and severe diarrhea associated with CDI (PMID: 27657131). While the FDA-approved antibody Bezlotoxumab neutralizes the toxin by binding its C-terminal domain, the GTD remains a critical target for intracellular-acting small molecules and nanobodies (PMID: 25151253). Direct inhibition of the GTD enzymatic activity is a promising strategy to prevent the cellular damage that occurs after the toxin has already entered the host cell. Research into this domain also focuses on its structural transitions and the specific residues involved in substrate recognition to facilitate the design of high-affinity inhibitors.

Other names

TcdB effector domainGlucosyltransferase domain of Toxin BTcdB(1-543)Rho-glucosylating toxin B

The domain catalyzes the transfer of a glucose moiety from UDP-glucose to a conserved threonine residue (Thr37 in Rho, Thr35 in Rac/Cdc42) on Rho family GTPases, leading to their inactivation and subsequent disruption of host cell signaling and structural integrity (PMID: 10601302).