Author
LEE, KWANGKOOK - Sanford And Burnham Medical Research Institute | |
GU, SHENGYAN - Sanford And Burnham Medical Research Institute | |
JIN, LEI - Sanford And Burnham Medical Research Institute | |
LE, THI TUC NGHI - Hannover University | |
Cheng, Luisa | |
STROTMEIER, JASMIN - Hannover University | |
KRUE, ANNA - Hannover University | |
PERRY, KAY - Cornell University | |
YAO, GUORUI - Sanford And Burnham Medical Research Institute | |
RUMMEL, ANDREAS - Sanford And Burnham Medical Research Institute | |
JIN, RONGSHENG - Sanford And Burnham Medical Research Institute |
Submitted to: PLoS Pathogens
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 7/11/2013 Publication Date: 10/10/2013 Citation: Lee, K., Gu, S., Jin, L., Le, T., Cheng, L.W., Strotmeier, J., Krue, A.M., Perry, K., Yao, G., Rummel, A., Jin, R. 2013. Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathogens. 9(10):e1003690. DOI: 10.1371/journal.ppat.1003690. Interpretive Summary: In this study, scientists resolved the structure of the large botulinum neurotoxin complex. The structure revealed toxin domains important in protection from degradation in the harsh environment of the intestinal tract and in intestinal absorption. Researchers also identified sugar inhibitors of toxin-intestinal binding, showing a new way to counteract toxin ingestion. Technical Abstract: Botulinum neurotoxins (BoNTs) are highly potent oral poisons produced by Clostridium botulinum. BoNTs are secreted along with several auxiliary proteins forming progenitor toxin complexes (PTC). Here, we report the structure of a ~760 kDa 14-subunit PTC using a combination of X-ray crystallography and electron microscopy. Structural and functional studies showed that the PTC consists of two relatively independent sub-complexes that are responsible for BoNT protection and absorption in the harsh environment of the gastrointestinal tract. Moreover, efficient BoNT intestinal absorption is mediated by the PTC’s nine glycan-binding sites through multivalent interactions with host carbohydrate receptors lining the intestine. Importantly, we identified an inhibitory monosaccharide that blocked oral BoNT intoxication in mice, thus suggesting that receptor mimicry approaches could be used as novel countermeasures for BoNTs. |