Structure of the full-length Clostridium difficile toxin B
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. In this paper, 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. In conclusion, 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.
- Authors:
-
[1];
[1];
[1];
[2];
[1];
[4];
[2];
[5];
[1]
- Univ. of California, Irvine, CA (United States)
- Stony Brook Univ., NY (United States)
- Univ. of Maryland Baltimore, Baltimore, MD (United States)
- SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., CA (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1560657
- Grant/Contract Number:
- AC02-76SF00515; AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Structural & Molecular Biology
- Additional Journal Information:
- Journal Volume: 26; Journal Issue: 8; Journal ID: ISSN 1545-9993
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Chen, Peng, Lam, Kwok-ho, Liu, Zheng, Mindlin, Frank A., Chen, Baohua, Gutierrez, Craig B., Huang, Lan, Zhang, Yongrong, Hamza, Therwa, Feng, Hanping, Matsui, Tsutomu, Bowen, Mark E., Perry, Kay, and Jin, Rongsheng. Structure of the full-length Clostridium difficile toxin B. United States: N. p., 2019.
Web. https://doi.org/10.1038/s41594-019-0268-0.
Chen, Peng, Lam, Kwok-ho, Liu, Zheng, Mindlin, Frank A., Chen, Baohua, Gutierrez, Craig B., Huang, Lan, Zhang, Yongrong, Hamza, Therwa, Feng, Hanping, Matsui, Tsutomu, Bowen, Mark E., Perry, Kay, & Jin, Rongsheng. Structure of the full-length Clostridium difficile toxin B. United States. https://doi.org/10.1038/s41594-019-0268-0
Chen, Peng, Lam, Kwok-ho, Liu, Zheng, Mindlin, Frank A., Chen, Baohua, Gutierrez, Craig B., Huang, Lan, Zhang, Yongrong, Hamza, Therwa, Feng, Hanping, Matsui, Tsutomu, Bowen, Mark E., Perry, Kay, and Jin, Rongsheng. Mon .
"Structure of the full-length Clostridium difficile toxin B". United States. https://doi.org/10.1038/s41594-019-0268-0. https://www.osti.gov/servlets/purl/1560657.
@article{osti_1560657,
title = {Structure of the full-length Clostridium difficile toxin B},
author = {Chen, Peng and Lam, Kwok-ho and Liu, Zheng and Mindlin, Frank A. and Chen, Baohua and Gutierrez, Craig B. and Huang, Lan and Zhang, Yongrong and Hamza, Therwa and Feng, Hanping and Matsui, Tsutomu and Bowen, Mark E. and Perry, Kay and Jin, Rongsheng},
abstractNote = {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. In this paper, 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. In conclusion, 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.},
doi = {10.1038/s41594-019-0268-0},
journal = {Nature Structural & Molecular Biology},
number = 8,
volume = 26,
place = {United States},
year = {2019},
month = {7}
}
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