8b0b - Revision history

OCA at 08:15, 7 February 2024

2024-02-07T08:15:24Z

←Older revision		Revision as of 08:15, 7 February 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[8b0b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8B0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B0B FirstGlance]. <br>		<table><tr><td colspan='2'>[[8b0b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8B0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B0B FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OUU:(1~{S},2~{R},3~{R},4~{S},6~{S})-2-(2-acetamidoethoxy)-3,4,6-tris(oxidanyl)cyclohexane-1-carboxylic+acid'>OUU</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]] 1.95Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OUU:(1~{S},2~{R},3~{R},4~{S},6~{S})-2-(2-acetamidoethoxy)-3,4,6-tris(oxidanyl)cyclohexane-1-carboxylic+acid'>OUU</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=8b0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b0b OCA], [https://pdbe.org/8b0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b0b RCSB], [https://www.ebi.ac.uk/pdbsum/8b0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b0b 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=8b0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b0b OCA], [https://pdbe.org/8b0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b0b RCSB], [https://www.ebi.ac.uk/pdbsum/8b0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b0b ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/HPSE_HUMAN HPSE_HUMAN] Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.<ref>PMID:12213822</ref> <ref>PMID:12773484</ref> <ref>PMID:15044433</ref> <ref>PMID:16452201</ref> <ref>PMID:18557927</ref> <ref>PMID:18798279</ref> <ref>PMID:19244131</ref> <ref>PMID:20097882</ref> <ref>PMID:20181948</ref> <ref>PMID:20309870</ref> <ref>PMID:20561914</ref> <ref>PMID:21131364</ref>		[https://www.uniprot.org/uniprot/HPSE_HUMAN HPSE_HUMAN] Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.<ref>PMID:12213822</ref> <ref>PMID:12773484</ref> <ref>PMID:15044433</ref> <ref>PMID:16452201</ref> <ref>PMID:18557927</ref> <ref>PMID:18798279</ref> <ref>PMID:19244131</ref> <ref>PMID:20097882</ref> <ref>PMID:20181948</ref> <ref>PMID:20309870</ref> <ref>PMID:20561914</ref> <ref>PMID:21131364</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with beta-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over beta-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs.
-
-	4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors.,Borlandelli V, Armstrong Z, Nin-Hill A, Codee J, Raich L, Artola M, Rovira C, Davies G, Overkleeft HS ChemMedChem. 2022 Dec 19. doi: 10.1002/cmdc.202200580. PMID:36533564<ref>PMID:36533564</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 8b0b" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 09:04, 28 December 2022

2022-12-28T09:04:16Z

←Older revision		Revision as of 09:04, 28 December 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 8b0b is ~~ON HOLD until Paper~~ Publication	+	==Crystal structure of human heparanase in complex with covalent inhibitor VB151==
		+	<StructureSection load='8b0b' size='340' side='right'caption='[[8b0b]], [[Resolution\|resolution]] 1.95Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8b0b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8B0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B0B FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OUU:(1~{S},2~{R},3~{R},4~{S},6~{S})-2-(2-acetamidoethoxy)-3,4,6-tris(oxidanyl)cyclohexane-1-carboxylic+acid'>OUU</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=8b0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b0b OCA], [https://pdbe.org/8b0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b0b RCSB], [https://www.ebi.ac.uk/pdbsum/8b0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b0b ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/HPSE_HUMAN HPSE_HUMAN] Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.<ref>PMID:12213822</ref> <ref>PMID:12773484</ref> <ref>PMID:15044433</ref> <ref>PMID:16452201</ref> <ref>PMID:18557927</ref> <ref>PMID:18798279</ref> <ref>PMID:19244131</ref> <ref>PMID:20097882</ref> <ref>PMID:20181948</ref> <ref>PMID:20309870</ref> <ref>PMID:20561914</ref> <ref>PMID:21131364</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with beta-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over beta-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs.

-	~~Authors: Armstrong~~, Z., ~~Davies~~, G.J.	+	4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors.,Borlandelli V, Armstrong Z, Nin-Hill A, Codee J, Raich L, Artola M, Rovira C, Davies G, Overkleeft HS ChemMedChem. 2022 Dec 19. doi: 10.1002/cmdc.202200580. PMID:36533564<ref>PMID:36533564</ref>

-	~~Description: Crystal structure~~ of ~~human heparanase in complex with covalent inhibitor VB151~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Davies, G.J~~]]	+	<div class="pdbe-citations 8b0b" style="background-color:#fffaf0;"></div>
-	[[Category: Armstrong, Z]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Armstrong Z]]
		+	[[Category: Davies GJ]]

OCA at 03:47, 26 October 2022

2022-10-26T03:47:26Z

←Older revision		Revision as of 03:47, 26 October 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8b0b is ON HOLD	+	The entry 8b0b is ON HOLD until Paper Publication

	Authors: Armstrong, Z., Davies, G.J.		Authors: Armstrong, Z., Davies, G.J.

OCA: Protected "8b0b" [edit=sysop:move=sysop]

2022-09-14T05:41:43Z

Protected "8b0b" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:41, 14 September 2022

OCA: New page: '''Unreleased structure''' The entry 8b0b is ON HOLD Authors: Armstrong, Z., Davies, G.J. Description: Crystal structure of human heparanase in complex with covalent inhibitor VB151 [[...

2022-09-14T05:41:42Z

New page: '''Unreleased structure''' The entry 8b0b is ON HOLD Authors: Armstrong, Z., Davies, G.J. Description: Crystal structure of human heparanase in complex with covalent inhibitor VB151 [[...

New page

'''Unreleased structure'''

The entry 8b0b is ON HOLD

Authors: Armstrong, Z., Davies, G.J.

Description: Crystal structure of human heparanase in complex with covalent inhibitor VB151
[[Category: Unreleased Structures]]
[[Category: Davies, G.J]]
[[Category: Armstrong, Z]]