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| | ==Binding domain of BoNT/A complexed with ganglioside== | | ==Binding domain of BoNT/A complexed with ganglioside== |
| - | <StructureSection load='5tpc' size='340' side='right' caption='[[5tpc]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='5tpc' size='340' side='right'caption='[[5tpc]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tpc]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TPC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TPC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tpc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TPC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TPC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=NGA:N-ACETYL-D-GALACTOSAMINE'>NGA</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2vu9|2vu9]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=NGA:N-ACETYL-D-GALACTOSAMINE'>NGA</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Bontoxilysin Bontoxilysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.69 3.4.24.69] </span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5tpc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tpc OCA], [https://pdbe.org/5tpc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tpc RCSB], [https://www.ebi.ac.uk/pdbsum/5tpc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tpc ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5tpc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tpc OCA], [http://pdbe.org/5tpc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tpc RCSB], [http://www.ebi.ac.uk/pdbsum/5tpc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tpc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BXA1_CLOBO BXA1_CLOBO]] Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure. | + | [https://www.uniprot.org/uniprot/BXA1_CLOBH BXA1_CLOBH] Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5tpc" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5tpc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bontoxilysin]] | + | [[Category: Clostridium botulinum]] |
| - | [[Category: Berntsson, R P.A]] | + | [[Category: Large Structures]] |
| - | [[Category: Stenmark, P]] | + | [[Category: Berntsson RP-A]] |
| - | [[Category: Svensson, L M]] | + | [[Category: Stenmark P]] |
| - | [[Category: Binding domain]] | + | [[Category: Svensson LM]] |
| - | [[Category: Ganglioside binding]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Lectin]]
| + | |
| Structural highlights
Function
BXA1_CLOBH Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure.
Publication Abstract from PubMed
The highly poisonous botulinum neurotoxins, produced by the bacterium Clostridium botulinum, act on their hosts by a high-affinity association to two receptors on neuronal cell surfaces as the first step of invasion. The glycan motifs of gangliosides serve as initial coreceptors for these protein complexes, whereby a membrane protein receptor is bound. Herein we set out to characterize the carbohydrate minimal binding epitope of the botulinum neurotoxin serotype A. By means of ligand-based NMR spectroscopy, X-ray crystallography, computer simulations, and isothermal titration calorimetry, a screening of ganglioside analogues together with a detailed characterization of various carbohydrate ligand complexes with the toxin were accomplished. We show that the representation of the glycan epitope to the protein affects the details of binding. Notably, both branches of the oligosaccharide GD1a can associate to botulinum neurotoxin serotype A when expressed as individual trisaccharides. It is, however, the terminal branch of GD1a as well as this trisaccharide motif alone, corresponding to the sialyl-Thomsen-Friedenreich antigen, that represents the active ligand epitope, and these compounds bind to the neurotoxin with a high degree of predisposition but with low affinities. This finding does not correlate with the oligosaccharide moieties having a strong contribution to the total affinity, which was expected to be the case. We here propose that the glycan part of the ganglioside receptors mainly provides abundance and specificity, whereas the interaction with the membrane itself and protein receptor brings about the strong total binding of the toxin to the neuronal membrane.
Glycans Confer Specificity to the Recognition of Ganglioside Receptors by Botulinum Neurotoxin A.,Hamark C, Berntsson RP, Masuyer G, Henriksson LM, Gustafsson R, Stenmark P, Widmalm G J Am Chem Soc. 2017 Jan 11;139(1):218-230. doi: 10.1021/jacs.6b09534. Epub 2016, Dec 27. PMID:27958736[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hamark C, Berntsson RP, Masuyer G, Henriksson LM, Gustafsson R, Stenmark P, Widmalm G. Glycans Confer Specificity to the Recognition of Ganglioside Receptors by Botulinum Neurotoxin A. J Am Chem Soc. 2017 Jan 11;139(1):218-230. doi: 10.1021/jacs.6b09534. Epub 2016, Dec 27. PMID:27958736 doi:http://dx.doi.org/10.1021/jacs.6b09534
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