View source for 8jyg


==Crystal structure of Human HPSE1 in complex with inhibitor==
<StructureSection load='8jyg' size='340' side='right'caption='[[8jyg]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8jyg]] 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=8JYG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JYG 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]] 2&#8491;</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=V8R:(5~{S},6~{R},7~{S},8~{S})-6,7,8-tris(oxidanyl)-2-[2-(3-phenoxyphenyl)ethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic+acid'>V8R</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=8jyg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jyg OCA], [https://pdbe.org/8jyg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jyg RCSB], [https://www.ebi.ac.uk/pdbsum/8jyg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jyg 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> 
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== Publication Abstract from PubMed ==
Heparanase-1 (HPSE1) is an endo-beta-d-glucuronidase that is the only mammalian enzyme known to cleave heparan sulfate (HS) of heparan sulfate proteoglycans (HSPG), a key component of the glycocalyx layer of the vascular endothelium matrix. Inhibition of HPSE1 has therapeutic potential for cancer and proteinuric kidney diseases. We previously reported that 2 showed a moderate potency as an HPSE1 inhibitor and an issue of selectivity against exo-beta-d-glucuronidase (GUSbeta) and glucocerebrosidase (GBA) remained. A structure-based lead optimization of 2 using X-ray co-crystal structure analysis and fragment molecular orbital calculation resulted in 4e, which showed a more than 7-fold increase in HPSE1 inhibitory activity. The subsequent introduction of a methyl group into the 6-hydroxy group of 4e resulted in 18 with reduced inhibitory activities against GUSbeta and GBA while maintaining the inhibitory activity against HPSE1. The inhibitory activities of 18 against serum HPSE1 in mice were significant and lasted for 4 h at doses of 3, 30, and 100 mg/kg. Compound 18 could be a novel lead compound for HPSE1 inhibitors with improved inhibitory activity against HPSE1 and increased HPSE1 selectivity over GUSbeta and GBA.

Structure-based lead optimization to improve potency and selectivity of a novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid series of heparanase-1 inhibitor.,Imai Y, Suzuki R, Wakasugi D, Matsuda D, Tanaka-Yamamoto N, Ohki Y, Mima M, Endo M, Tabata R, Matsuzawa H, Hasegawa Y, Kato S, Sugisaki M, Miyagawa H, Fujimoto N, Fukunaga T, Kato S, Takahashi T, Kakinuma H Bioorg Med Chem. 2023 Oct 1;93:117460. doi: 10.1016/j.bmc.2023.117460. Epub 2023 , Aug 26. PMID:37660465<ref>PMID:37660465</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8jyg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fujimoto N]]
[[Category: Imai Y]]
[[Category: Mima M]]