期刊
PLOS PATHOGENS
卷 9, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1003690
关键词
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资金
- National Institute of Allergy and Infectious Diseases (NIAID) [5R01AI091823, U54 AI065359]
- Deutsche Forschungsgemeinschaft [DFG Exzellenzinitiative GSC 108]
- Swiss Federal Office for Civil Protection (BABS) [353003325]
- United States Department of Agriculture CRIS project [5325-42000-048-00D]
- National Center for Research Resources (NCRR) [5P41RR015301-10]
- National Institute of General Medical Sciences (NIGMS) [8 P41 GM103403-10]
- U.S. Department of Energy (DOE) [DE-AC02-06CH11357]
- DOE Office of Biological and Environmental Research
- NIGMS [P41GM103393]
- NCRR [P41RR001209]
- NIH at UCLA [1S10RR23057]
- NIH
- Deutsche Forschungsgemeinschaft DFG
Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. BoNTs are released together with several auxiliary proteins as progenitor toxin complexes (PTCs) to become highly potent oral poisons. Here, we report the structure of a similar to 760 kDa 14-subunit large PTC of serotype A (L-PTC/A) and reveal insight into its absorption mechanism. Using a combination of X-ray crystallography, electron microscopy, and functional studies, we found that L-PTC/A consists of two structurally and functionally independent sub-complexes. A hetero-dimeric 290 kDa complex protects BoNT, while a hetero-dodecameric 470 kDa complex facilitates its absorption in the harsh environment of the gastrointestinal tract. BoNT absorption is mediated by nine glycan-binding sites on the dodecameric sub-complex that forms multivalent interactions with carbohydrate receptors on intestinal epithelial cells. We identified monosaccharides that blocked oral BoNT intoxication in mice, which suggests a new strategy for the development of preventive countermeasures for BoNTs based on carbohydrate receptor mimicry.
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