9OHE
CryoEM structure of apo Toxin B (TcdB) from Clostridioides difficile in the closed CROP state
Summary for 9OHE
| Entry DOI | 10.2210/pdb9ohe/pdb |
| EMDB information | 70488 |
| Descriptor | Toxin B (1 entity in total) |
| Functional Keywords | clostridioides difficile, toxin b, tcdb, toxin |
| Biological source | Clostridioides difficile |
| Total number of polymer chains | 1 |
| Total formula weight | 270767.28 |
| Authors | |
| Primary citation | Miletic, S.,Icho, S.,Li, Z.,Tam, J.,Rose, E.C.,Perkins, C.E.,Nakhi, A.,Yang, X.,Hang, H.C.,Rubinstein, J.L.,Dosa, P.I.,Theriot, C.M.,Melnyk, R.A. Structure-guided design of a synthetic bile acid that inhibits Clostridioides difficile TcdB toxin. Nat Microbiol, 10:3215-3228, 2025 Cited by PubMed Abstract: Intestinal bile acids are a family of host and microbiota metabolites that can directly inhibit toxin B (TcdB), the primary virulence factor of Clostridioides difficile that causes infectious diarrhoea and colitis. However, the mechanism underlying the inhibition is unclear. Here we used cryogenic electron microscopy and determined the structure of TcdB bound to inhibitory bile acids cholic acid (methyl ester) and taurochenodeoxycholic acid at 2.9 Å and 3.3 Å resolution, respectively. These structures revealed that bile acids lock the C-terminal CROP domain of TcdB in a conformation that allosterically masks the two receptor-binding sites and prevents target cell recognition. Guided by the structure, we synthesized gut-restricted bile acid derivatives, designed to evade the bile acid reuptake transporters within the gut. One of the derivatives, sBA-2, was retained within the gut upon oral dosing and protected mice from toxin-induced C. difficile disease pathology. Our study uncovers the structural basis of inhibition of TcdB by bile acids and its analogues, paving the way for the development of orally deliverable therapeutics against C. difficile. PubMed: 41254394DOI: 10.1038/s41564-025-02179-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.59 Å) |
Structure validation
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