OCA at 10:25, 10 January 2024

OCA — Wed, 10 Jan 2024 10:25:27 GMT

←Older revision		Revision as of 10:25, 10 January 2024
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-	'''Unreleased structure'''

-	~~The entry~~ 8ohr is ~~ON HOLD until Paper~~ Publication	+	==Crystal structure of human heparanase in complex with glucuronic acid configured 3-geminal diol iminosugar inhibitor==
		+	<StructureSection load='8ohr' size='340' side='right'caption='[[8ohr]], [[Resolution\|resolution]] 1.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8ohr]] 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=8OHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OHR FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.8Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=VP5:(3~{S},4~{R})-4,5,5-tris(oxidanyl)piperidine-3-carboxylic+acid'>VP5</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=8ohr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ohr OCA], [https://pdbe.org/8ohr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ohr RCSB], [https://www.ebi.ac.uk/pdbsum/8ohr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ohr 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 ==
		+	Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, beta-d-glucuronidases, and N-acetyl-glucosaminidases. The mode of inhibition of glucuronidases, in contrast to sialidases, has long been enigmatic as siastatin B appears too bulky and incorrectly substituted to be accommodated within a beta-d-glucuronidase active site pocket. Herein, we show through crystallographic analysis of protein-inhibitor complexes that siastatin B generates both a hemiaminal and a 3-geminal diol iminosugar (3-GDI) that are, rather than the parent compound, directly responsible for enzyme inhibition. The hemiaminal product is the first observation of a natural product that belongs to the noeuromycin class of inhibitors. Additionally, the 3-GDI represents a new and potent class of the iminosugar glycosidase inhibitor. To substantiate our findings, we synthesized both the gluco- and galacto-configured 3-GDIs and characterized their binding both structurally and kinetically to exo-beta-d-glucuronidases and the anticancer target human heparanase. This revealed submicromolar inhibition of exo-beta-d-glucuronidases and an unprecedented binding mode by this new class of inhibitor. Our results reveal the mechanism by which siastatin B acts as a broad-spectrum glycosidase inhibitor, identify a new class of glycosidase inhibitor, and suggest new functionalities that can be incorporated into future generations of glycosidase inhibitors.

-	~~Authors: Armstrong, Z~~., ~~Yurong~~, C., Wu, L., ~~Overkleeft~~, ~~H.S.~~, Davies, G.J.	+	Molecular Basis for Inhibition of Heparanases and beta-Glucuronidases by Siastatin B.,Chen Y, van den Nieuwendijk AMCH, Wu L, Moran E, Skoulikopoulou F, van Riet V, Overkleeft HS, Davies GJ, Armstrong Z J Am Chem Soc. 2023 Dec 20. doi: 10.1021/jacs.3c04162. PMID:38118176<ref>PMID:38118176</ref>

-	~~Description: Crystal structure~~ of ~~human heparanase in complex with glucuronic acid configured 3~~-~~geminal diol iminosugar inhibitor~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Yurong, C~~]]	+	<div class="pdbe-citations 8ohr" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Overkleeft, H.S~~]]	+	== References ==
-	[[Category: ~~Wu, L~~]]	+	<references/>
-	[[Category: ~~Davies, G.J~~]]	+	__TOC__
-	[[Category: ~~Armstrong, Z~~]]	+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Armstrong Z]]
		+	[[Category: Davies GJ]]
		+	[[Category: Overkleeft HS]]
		+	[[Category: Wu L]]
		+	[[Category: Yurong C]]

OCA at 15:11, 26 April 2023

OCA — Wed, 26 Apr 2023 15:11:51 GMT

←Older revision		Revision as of 15:11, 26 April 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Armstrong, Z., Yurong, C., Wu, L., Overkleeft, H.S., Davies, G.J.		Authors: Armstrong, Z., Yurong, C., Wu, L., Overkleeft, H.S., Davies, G.J.

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

OCA — Wed, 29 Mar 2023 05:07:46 GMT

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

←Older revision

Revision as of 05:07, 29 March 2023

OCA: New page: '''Unreleased structure''' The entry 8ohr is ON HOLD Authors: Armstrong, Z., Yurong, C., Wu, L., Overkleeft, H.S., Davies, G.J. Description: Crystal structure of human heparanase in co...

OCA — Wed, 29 Mar 2023 05:07:45 GMT

New page: '''Unreleased structure''' The entry 8ohr is ON HOLD Authors: Armstrong, Z., Yurong, C., Wu, L., Overkleeft, H.S., Davies, G.J. Description: Crystal structure of human heparanase in co...

New page

'''Unreleased structure'''

The entry 8ohr is ON HOLD

Authors: Armstrong, Z., Yurong, C., Wu, L., Overkleeft, H.S., Davies, G.J.

Description: Crystal structure of human heparanase in complex with glucuronic acid configured 3-geminal diol iminosugar inhibitor
[[Category: Unreleased Structures]]
[[Category: Yurong, C]]
[[Category: Overkleeft, H.S]]
[[Category: Wu, L]]
[[Category: Davies, G.J]]
[[Category: Armstrong, Z]]

8ohr - Revision history

OCA at 10:25, 10 January 2024

OCA at 15:11, 26 April 2023

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

OCA: New page: '''Unreleased structure''' The entry 8ohr is ON HOLD Authors: Armstrong, Z., Yurong, C., Wu, L., Overkleeft, H.S., Davies, G.J. Description: Crystal structure of human heparanase in co...