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==Crystal structure of the binding domain of Botulinum Neurotoxin type B in complex with human synaptotagmin 1==
==Crystal structure of the binding domain of Botulinum Neurotoxin type B in complex with human synaptotagmin 1==
<StructureSection load='6g5k' size='340' side='right' caption='[[6g5k]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='6g5k' size='340' side='right'caption='[[6g5k]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6g5k]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_botulinus"_van_ermengem_1896 "bacillus botulinus" van ermengem 1896]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G5K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G5K FirstGlance]. <br>
<table><tr><td colspan='2'>[[6g5k]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G5K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G5K FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">botB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1491 "Bacillus botulinus" van Ermengem 1896])</td></tr>
</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=6g5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5k OCA], [https://pdbe.org/6g5k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g5k RCSB], [https://www.ebi.ac.uk/pdbsum/6g5k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5k ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6g5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5k OCA], [http://pdbe.org/6g5k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g5k RCSB], [http://www.ebi.ac.uk/pdbsum/6g5k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5k ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/BXB_CLOBO BXB_CLOBO]] Botulinum toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves the '76-Gln-|-Phe-77' bond of synaptobrevin-2. [[http://www.uniprot.org/uniprot/SYT1_HUMAN SYT1_HUMAN]] May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2.
[[https://www.uniprot.org/uniprot/BXB_CLOBO BXB_CLOBO]] Botulinum toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves the '76-Gln-|-Phe-77' bond of synaptobrevin-2.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Although botulinum neurotoxin serotype A (BoNT/A) products are common treatments for various disorders, there is only one commercial BoNT/B product, whose low potency, likely stemming from low affinity toward its human receptor synaptotagmin 2 (hSyt2), has limited its therapeutic usefulness. We express and characterize two full-length recombinant BoNT/B1 proteins containing designed mutations E1191M/S1199Y (rBoNT/B1MY) and E1191Q/S1199W (rBoNT/B1QW) that enhance binding to hSyt2. In preclinical models including human-induced pluripotent stem cell neurons and a humanized transgenic mouse, this increased hSyt2 affinity results in high potency, comparable to that of BoNT/A. Last, we solve the cocrystal structure of rBoNT/B1MY in complex with peptides of hSyt2 and its homolog hSyt1. We demonstrate that neuronal surface receptor binding limits the clinical efficacy of unmodified BoNT/B and that modified BoNT/B proteins have promising clinical potential.


Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models.,Elliott M, Favre-Guilmard C, Liu SM, Maignel J, Masuyer G, Beard M, Boone C, Carre D, Kalinichev M, Lezmi S, Mir I, Nicoleau C, Palan S, Perier C, Raban E, Zhang S, Dong M, Stenmark P, Krupp J Sci Adv. 2019 Jan 16;5(1):eaau7196. doi: 10.1126/sciadv.aau7196. eCollection 2019, Jan. PMID:30746458<ref>PMID:30746458</ref>
==See Also==
 
*[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
*[[Synaptotagmin 3D structures|Synaptotagmin 3D structures]]
</div>
<div class="pdbe-citations 6g5k" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bacillus botulinus van ermengem 1896]]
[[Category: Clostridium botulinum]]
[[Category: Bontoxilysin]]
[[Category: Homo sapiens]]
[[Category: Beard, M]]
[[Category: Large Structures]]
[[Category: Carre, D]]
[[Category: Beard M]]
[[Category: Dong, M]]
[[Category: Carre D]]
[[Category: Elliot, M]]
[[Category: Dong M]]
[[Category: Favre-Guilmard, C]]
[[Category: Elliot M]]
[[Category: Kalinichev, M]]
[[Category: Favre-Guilmard C]]
[[Category: Krupp, J]]
[[Category: Kalinichev M]]
[[Category: Lezmi, S]]
[[Category: Krupp J]]
[[Category: Liu, S M]]
[[Category: Lezmi S]]
[[Category: Maignel, J]]
[[Category: Liu SM]]
[[Category: Masuyer, G]]
[[Category: Maignel J]]
[[Category: Mir, I]]
[[Category: Masuyer G]]
[[Category: Nicoleau, C]]
[[Category: Mir I]]
[[Category: Palan, S]]
[[Category: Nicoleau C]]
[[Category: Perier, C]]
[[Category: Palan S]]
[[Category: Raban, E]]
[[Category: Perier C]]
[[Category: Stenmark, P]]
[[Category: Raban E]]
[[Category: Botulinum toxin]]
[[Category: Stenmark P]]
[[Category: Neurotoxin]]
[[Category: Protein engineering]]
[[Category: Receptor binding]]
[[Category: Toxin]]

Revision as of 19:45, 7 September 2022

Crystal structure of the binding domain of Botulinum Neurotoxin type B in complex with human synaptotagmin 1Crystal structure of the binding domain of Botulinum Neurotoxin type B in complex with human synaptotagmin 1

Structural highlights

6g5k is a 4 chain structure with sequence from Clostridium botulinum and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[BXB_CLOBO] Botulinum toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves the '76-Gln-|-Phe-77' bond of synaptobrevin-2.

See Also

6g5k, resolution 2.00Å

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