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Structure paper

TitleStructure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity.
Journal, issue, pagesPLoS Pathog, Vol. 9, Issue 10, Page e1003690, Year 2013
Publish dateOct 10, 2013
AuthorsKwangkook Lee / Shenyan Gu / Lei Jin / Thi Tuc Nghi Le / Luisa W Cheng / Jasmin Strotmeier / Anna Magdalena Kruel / Guorui Yao / Kay Perry / Andreas Rummel / Rongsheng Jin /
PubMed AbstractBotulinum 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 ...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 ∼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.
External linksPLoS Pathog / PubMed:24130488 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.055 - 30.0 Å
Structure data

EMDB-2416:
Negative staining 3D-EM of the HA complex of Botulinum toxin type A
Method: EM (single particle) / Resolution: 30.0 Å

EMDB-2417:
Negative staining 3D-EM of the progenitor toxin complex (PTC) of Botulinum toxin type A
Method: EM (single particle) / Resolution: 30.0 Å

PDB-4lo0:
Apo HA17-HA33
Method: X-RAY DIFFRACTION / Resolution: 2.055 Å

PDB-4lo1:
HA17-HA33-Gal
Method: X-RAY DIFFRACTION / Resolution: 2.254 Å

PDB-4lo2:
HA17-HA33-Lac
Method: X-RAY DIFFRACTION / Resolution: 2.254 Å

PDB-4lo3:
HA17-HA33-LacNac
Method: X-RAY DIFFRACTION / Resolution: 2.249 Å

PDB-4lo4:
Apo HA-70
Method: X-RAY DIFFRACTION / Resolution: 2.871 Å

PDB-4lo5:
HA70-alpha2,3-SiaLC
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

PDB-4lo6:
HA70-alpha2,6-SiaLC
Method: X-RAY DIFFRACTION / Resolution: 2.3 Å

PDB-4lo7:
HA70(D3)-HA17-HA33
Method: X-RAY DIFFRACTION / Resolution: 3.73 Å

PDB-4lo8:
HA70(D3)-HA17
Method: X-RAY DIFFRACTION / Resolution: 2.4 Å

Chemicals

ChemComp-HOH:
WATER

ChemComp-GAL:
beta-D-galactopyranose

ChemComp-CL:
Unknown entry

Source
  • clostridium botulinum (bacteria)
KeywordsPROTEIN TRANSPORT / progenitor toxin complex / botulinum neurotoxin / botulism / neurotoxin associated protein / hemagglutinin / carbohydrate/sugar binding / secreted protein

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