6g5g

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of an engineered Botulinum Neurotoxin type B mutant E1191M/S1199Y in complex with human synaptotagmin 2

Structural highlights

6g5g is a 3 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.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	, , , , ,
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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models. Sci Adv. 2019 Jan 16;5(1):eaau7196. doi: 10.1126/sciadv.aau7196. eCollection 2019, Jan. PMID:30746458 doi:http://dx.doi.org/10.1126/sciadv.aau7196

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6g5g"

@@ Line 3: / Line 3: @@
 <StructureSection load='6g5g' size='340' side='right'caption='[[6g5g]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6g5g]] is a 3 chain structure with sequence from [https://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=6G5G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G5G FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6g5g]] is a 3 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=6G5G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G5G FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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]] 2&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">botB ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1491 "Bacillus botulinus" van Ermengem 1896])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Bontoxilysin Bontoxilysin], with EC number [https://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=6g5g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5g OCA], [https://pdbe.org/6g5g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g5g RCSB], [https://www.ebi.ac.uk/pdbsum/6g5g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5g ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[https://www.uniprot.org/uniprot/SYT2_HUMAN SYT2_HUMAN]] Presynaptic congenital myasthenic syndromes. The disease is caused by variants affecting the gene represented in this entry.
 == Function ==
-[[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. [[https://www.uniprot.org/uniprot/SYT2_HUMAN SYT2_HUMAN]] Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties (By similarity). May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).[UniProtKB:P46097]<ref>PMID:23999003</ref>
+[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 ==
@@ Line 30: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Bacillus botulinus van ermengem 1896]]
+[[Category: Clostridium botulinum]]
-[[Category: Bontoxilysin]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Beard, M]]
+[[Category: Beard M]]
-[[Category: Carre, D]]
+[[Category: Carre D]]
-[[Category: Dong, M]]
+[[Category: Dong M]]
-[[Category: Elliot, M]]
+[[Category: Elliot M]]
-[[Category: Favre-Guilmard, C]]
+[[Category: Favre-Guilmard C]]
-[[Category: Kalinichev, M]]
+[[Category: Kalinichev M]]
-[[Category: Krupp, J]]
+[[Category: Krupp J]]
-[[Category: Lezmi, S]]
+[[Category: Lezmi S]]
-[[Category: Liu, S M]]
+[[Category: Liu SM]]
-[[Category: Maignel, J]]
+[[Category: Maignel J]]
-[[Category: Masuyer, G]]
+[[Category: Masuyer G]]
-[[Category: Mir, I]]
+[[Category: Mir I]]
-[[Category: Nicoleau, C]]
+[[Category: Nicoleau C]]
-[[Category: Palan, S]]
+[[Category: Palan S]]
-[[Category: Perier, C]]
+[[Category: Perier C]]
-[[Category: Raban, E]]
+[[Category: Raban E]]
-[[Category: Stenmark, P]]
+[[Category: Stenmark P]]
-[[Category: Botulinum toxin]]
-[[Category: Neurotoxin]]
-[[Category: Protein engineering]]
-[[Category: Receptor binding]]
-[[Category: Toxin]]

6g5g

From Proteopedia

Current revision

Crystal structure of an engineered Botulinum Neurotoxin type B mutant E1191M/S1199Y in complex with human synaptotagmin 2

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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