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Structure of the full-length Clostridium difficile toxin B.
- Source :
-
Nature structural & molecular biology [Nat Struct Mol Biol] 2019 Aug; Vol. 26 (8), pp. 712-719. Date of Electronic Publication: 2019 Jul 15. - Publication Year :
- 2019
-
Abstract
- Clostridium difficile is an opportunistic pathogen that establishes in the colon when the gut microbiota are disrupted by antibiotics or disease. C. difficile infection (CDI) is largely caused by two virulence factors, TcdA and TcdB. Here, we report a 3.87-Å-resolution crystal structure of TcdB holotoxin that captures a unique conformation of TcdB at endosomal pH. Complementary biophysical studies suggest that the C-terminal combined repetitive oligopeptides (CROPs) domain of TcdB is dynamic and can sample open and closed conformations that may facilitate modulation of TcdB activity in response to environmental and cellular cues during intoxication. Furthermore, we report three crystal structures of TcdB-antibody complexes that reveal how antibodies could specifically inhibit the activities of individual TcdB domains. Our studies provide novel insight into the structure and function of TcdB holotoxin and identify intrinsic vulnerabilities that could be exploited to develop new therapeutics and vaccines for the treatment of CDI.
- Subjects :
- Amino Acid Sequence
Antibodies, Neutralizing immunology
Antigen-Antibody Complex chemistry
Bacterial Proteins immunology
Bacterial Toxins immunology
Conserved Sequence
Crystallography, X-Ray
Endosomes chemistry
Hydrogen-Ion Concentration
Hydrophobic and Hydrophilic Interactions
Liposomes
Membrane Potentials
Models, Molecular
Peptide Fragments chemistry
Protein Binding
Protein Conformation
Sequence Alignment
Sequence Homology, Amino Acid
Bacterial Proteins chemistry
Bacterial Toxins chemistry
Clostridioides difficile chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1545-9985
- Volume :
- 26
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Nature structural & molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 31308519
- Full Text :
- https://doi.org/10.1038/s41594-019-0268-0