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| Article Authors: | Shenyan Gu; Sophie Rumpel; Jie Zhou; Jasmin Strotmeier; Hans Bigalke; Kay Perry; Charles B Shoemaker; Andreas Rummel; Rongsheng Jin |
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| Article Title: | Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. |
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| Reference ID: | 1024685 |
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| Abstract: | Botulinum neurotoxins (BoNTs) are highly poisonous substances that are also effective medicines. Accidental BoNT poisoning often occurs through ingestion of Clostridium botulinum-contaminated food. Here, we present the crystal structure of a BoNT in complex with a clostridial nontoxic nonhemagglutinin (NTNHA) protein at 2.7 angstroms. Biochemical and functional studies show that NTNHA provides large and multivalent binding interfaces to protect BoNT from gastrointestinal degradation. Moreover, the structure highlights key residues in BoNT that regulate complex assembly in a pH-dependent manner. Collectively, our findings define the molecular mechanisms by which NTNHA shields BoNT in the hostile gastrointestinal environment and releases it upon entry into the circulation. These results will assist in the design of small molecules for inhibiting oral BoNT intoxication and of delivery vehicles for oral administration of biologics. |
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| Affiliations: | Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. |
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| Date: | 2012 |
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| Reference Type: | Literature |
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| PubMed ID: | 22363010 |
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| Journal: | Science |
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| Journal Volume: | 335 |
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| Article Pages: | 977-81 |
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| Journal ISSN: | 1095-9203 |
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| Article Chemical List: | Bacterial Proteins;Multiprotein Complexes;Botulinum Toxins, Type A |
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| Article MeSH List: | Amino Acid Sequence; Bacterial Proteins(chemistry; metabolism); Binding Sites; Botulinum Toxins, Type A(chemistry; metabolism); Crystallography, X-Ray; Hydrogen-Ion Concentration; Models, Molecular; Molecular Sequence Data; Multiprotein Complexes(chemistry; metabolism); Mutagenesis; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Structure, Secondary |
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| Curation Last Updated: | 2013-05-28 22:44:02 |
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