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| | <StructureSection load='5l21' size='340' side='right'caption='[[5l21]], [[Resolution|resolution]] 1.68Å' scene=''> | | <StructureSection load='5l21' size='340' side='right'caption='[[5l21]], [[Resolution|resolution]] 1.68Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5l21]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Alpaca Alpaca] and [http://en.wikipedia.org/wiki/Clobh Clobh]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L21 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L21 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5l21]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_botulinum_A_str._Hall Clostridium botulinum A str. Hall] and [https://en.wikipedia.org/wiki/Vicugna_pacos Vicugna pacos]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L21 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L21 FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">botA, CBO0806, CLC_0862 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=441771 CLOBH])</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]] 1.68Å</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=5l21 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l21 OCA], [https://pdbe.org/5l21 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l21 RCSB], [https://www.ebi.ac.uk/pdbsum/5l21 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l21 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=5l21 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l21 OCA], [http://pdbe.org/5l21 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l21 RCSB], [http://www.ebi.ac.uk/pdbsum/5l21 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l21 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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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| | *[[Antibody 3D structures|Antibody 3D structures]] | | *[[Antibody 3D structures|Antibody 3D structures]] |
| | *[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]] | | *[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]] |
| | + | *[[3D structures of non-human antibody|3D structures of non-human antibody]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Alpaca]] | + | [[Category: Clostridium botulinum A str. Hall]] |
| - | [[Category: Bontoxilysin]]
| + | |
| - | [[Category: Clobh]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Jin, R]] | + | [[Category: Vicugna pacos]] |
| - | [[Category: Yao, G]] | + | [[Category: Jin R]] |
| - | [[Category: Bont-a-vhh complex]] | + | [[Category: Yao G]] |
| - | [[Category: Botulinum neurotoxin]]
| + | |
| - | [[Category: Neutralizing antibody]]
| + | |
| - | [[Category: Toxin]]
| + | |
| - | [[Category: Vhh]]
| + | |
| 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
Antibody treatment is currently the only available countermeasure for botulism, a fatal illness caused by flaccid paralysis of muscles due to botulinum neurotoxin (BoNT) intoxication. Among the seven major serotypes of BoNT/A-G, BoNT/A poses the most serious threat to humans because of its high potency and long duration of action. Prior to entering neurons and blocking neurotransmitter release, BoNT/A recognizes motoneurons via a dual-receptor binding process in which it engages both the neuron surface polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Previously, we identified a potent neutralizing antitoxin against BoNT/A1 termed ciA-C2, derived from a camelid heavy-chain-only antibody (VHH). In this study, we demonstrate that ciA-C2 prevents BoNT/A1 intoxication by inhibiting its binding to neuronal receptor SV2. Furthermore, we determined the crystal structure of ciA-C2 in complex with the receptor-binding domain of BoNT/A1 (HCA1) at 1.68 A resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on HCA1, causing direct interference of HCA1 interaction with both the N-glycan and peptide-moiety of SV2. Interestingly, this neutralization mechanism is similar to that of a monoclonal antibody in clinical trials, despite that ciA-C2 is more than 10-times smaller. Taken together, these results enlighten our understanding of BoNT/A1 interactions with its neuronal receptor, and further demonstrate that inhibiting toxin binding to the host receptor is an efficient countermeasure strategy.
A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding.,Yao G, Lam KH, Weisemann J, Peng L, Krez N, Perry K, Shoemaker CB, Dong M, Rummel A, Jin R Sci Rep. 2017 Aug 7;7(1):7438. doi: 10.1038/s41598-017-07457-5. PMID:28785006[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yao G, Lam KH, Weisemann J, Peng L, Krez N, Perry K, Shoemaker CB, Dong M, Rummel A, Jin R. A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding. Sci Rep. 2017 Aug 7;7(1):7438. doi: 10.1038/s41598-017-07457-5. PMID:28785006 doi:http://dx.doi.org/10.1038/s41598-017-07457-5
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