Peng Chen, K. Lam, Zheng Liu, Frank A. Mindlin, Baohua Chen, Craig B. Gutierrez, Lan Huang, Yongrong Zhang, Therwa Hamza, H. Feng, T. Matsui, M. Bowen, K. Perry, Rongsheng Jin
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Structure of the pore forming fragment of Clostridium difficile toxin B in complex with VHH 5D
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-A-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.
期刊介绍:
Nature Structural & Molecular Biology is a monthly journal that focuses on the functional and mechanistic understanding of how molecular components in a biological process work together. It serves as an integrated forum for structural and molecular studies. The journal places a strong emphasis on the functional and mechanistic understanding of how molecular components in a biological process work together. Some specific areas of interest include the structure and function of proteins, nucleic acids, and other macromolecules, DNA replication, repair and recombination, transcription, regulation of transcription and translation, protein folding, processing and degradation, signal transduction, and intracellular signaling.