View source for 8ohr


==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]] 1.80&Aring;' 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]] 1.8&#8491;</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>
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== 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.

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. 2024 Jan 10;146(1):125-133. doi: 10.1021/jacs.3c04162. Epub 2023 , Dec 20. PMID:38118176<ref>PMID:38118176</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Armstrong Z]]
[[Category: Davies GJ]]
[[Category: Overkleeft HS]]
[[Category: Wu L]]
[[Category: Yurong C]]