6g5f - Revision history

OCA at 11:50, 1 February 2024

OCA — Thu, 01 Feb 2024 11:50:57 GMT

←Older revision		Revision as of 11:50, 1 February 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6g5f]] 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=6G5F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G5F FirstGlance]. <br>		<table><tr><td colspan='2'>[[6g5f]] 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=6G5F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G5F FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</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]] 2.5Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></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=6g5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5f OCA], [https://pdbe.org/6g5f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g5f RCSB], [https://www.ebi.ac.uk/pdbsum/6g5f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5f ProSAT]</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=6g5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5f OCA], [https://pdbe.org/6g5f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g5f RCSB], [https://www.ebi.ac.uk/pdbsum/6g5f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5f ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== 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/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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 18:52, 7 September 2022

OCA — Wed, 07 Sep 2022 18:52:18 GMT

←Older revision		Revision as of 18:52, 7 September 2022
Line 9:		Line 9:
	== Function ==		== 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/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>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6g5f" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Botulinum neurotoxin 3D structures\|Botulinum neurotoxin 3D structures]]		*[[Botulinum neurotoxin 3D structures\|Botulinum neurotoxin 3D structures]]
	*[[Synaptotagmin 3D structures\|Synaptotagmin 3D structures]]		*[[Synaptotagmin 3D structures\|Synaptotagmin 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 16:45, 7 September 2022

OCA — Wed, 07 Sep 2022 16:45:34 GMT

←Older revision		Revision as of 16:45, 7 September 2022
Line 1:		Line 1:

	==Crystal structure of an engineered Botulinum Neurotoxin type B mutant E1191M/S1199Y in complex with human synaptotagmin 1==		==Crystal structure of an engineered Botulinum Neurotoxin type B mutant E1191M/S1199Y in complex with human synaptotagmin 1==
-	<StructureSection load='6g5f' size='340' side='right' caption='[[6g5f]], [[Resolution\|resolution]] 2.50Å' scene=''>	+	<StructureSection load='6g5f' size='340' side='right'caption='[[6g5f]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6g5f]] is a 3 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=6G5F OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6G5F FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6g5f]] 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=6G5F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G5F FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></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>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6g5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5f OCA], [https://pdbe.org/6g5f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g5f RCSB], [https://www.ebi.ac.uk/pdbsum/6g5f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5f 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=6g5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5f OCA], [~~http~~://pdbe.org/6g5f PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6g5f RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6g5f PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5f 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®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+	*[[Synaptotagmin 3D structures\|Synaptotagmin 3D structures]]
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6g5f" 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~~]]	+

OCA at 08:41, 21 February 2019

OCA — Thu, 21 Feb 2019 08:41:22 GMT

←Older revision		Revision as of 08:41, 21 February 2019
Line 3:		Line 3:
	<StructureSection load='6g5f' size='340' side='right' caption='[[6g5f]], [[Resolution\|resolution]] 2.50Å' scene=''>		<StructureSection load='6g5f' size='340' side='right' caption='[[6g5f]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6g5f]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G5F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G5F FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6g5f]] is a 3 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=6G5F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G5F FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></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>
	<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='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=6g5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5f OCA], [http://pdbe.org/6g5f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g5f RCSB], [http://www.ebi.ac.uk/pdbsum/6g5f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5f 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=6g5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5f OCA], [http://pdbe.org/6g5f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g5f RCSB], [http://www.ebi.ac.uk/pdbsum/6g5f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5f ProSAT]</span></td></tr>
Line 10:		Line 11:
	== 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.		[[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.
		+	<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>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6g5f" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Bacillus botulinus van ermengem 1896]]
	[[Category: Bontoxilysin]]		[[Category: Bontoxilysin]]
	[[Category: Beard, M]]		[[Category: Beard, M]]

OCA at 12:07, 16 January 2019

OCA — Wed, 16 Jan 2019 12:07:19 GMT

←Older revision		Revision as of 12:07, 16 January 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6g5f is ~~ON HOLD~~	+	==Crystal structure of an engineered Botulinum Neurotoxin type B mutant E1191M/S1199Y in complex with human synaptotagmin 1==
-		+	<StructureSection load='6g5f' size='340' side='right' caption='[[6g5f]], [[Resolution\|resolution]] 2.50Å' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6g5f]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G5F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G5F FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	<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=6g5f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5f OCA], [http://pdbe.org/6g5f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g5f RCSB], [http://www.ebi.ac.uk/pdbsum/6g5f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5f ProSAT]</span></td></tr>
		+	</table>
		+	== 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.
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Bontoxilysin]]
		+	[[Category: Beard, M]]
		+	[[Category: Carre, D]]
		+	[[Category: Dong, M]]
		+	[[Category: Elliot, M]]
		+	[[Category: Favre-Guilmard, C]]
		+	[[Category: Kalinichev, M]]
		+	[[Category: Krupp, J]]
		+	[[Category: Lezmi, S]]
		+	[[Category: Liu, S M]]
		+	[[Category: Maignel, J]]
		+	[[Category: Masuyer, G]]
		+	[[Category: Mir, I]]
		+	[[Category: Nicoleau, C]]
		+	[[Category: Palan, S]]
		+	[[Category: Perier, C]]
		+	[[Category: Raban, E]]
		+	[[Category: Stenmark, P]]
		+	[[Category: Botulinum toxin]]
		+	[[Category: Neurotoxin]]
		+	[[Category: Protein engineering]]
		+	[[Category: Receptor binding]]
		+	[[Category: Toxin]]

OCA: Protected "6g5f" [edit=sysop:move=sysop]

OCA — Wed, 11 Apr 2018 12:37:42 GMT

Protected "6g5f" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:37, 11 April 2018

OCA: New page: '''Unreleased structure''' The entry 6g5f is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 11 Apr 2018 12:37:41 GMT

New page: '''Unreleased structure''' The entry 6g5f is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6g5f is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]