8bac | pdb_00008bac

Crystal structure of human heparanase in complex with competitive inhibitor GD05

spinqualitylabelsall models 8bac, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8bac is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, NAG, SJ5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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. Publication Abstract from PubMed 1-Azasugar analogues of l-iduronic acid (l-IdoA) and d-glucuronic acid (d-GlcA) and their corresponding enantiomers have been synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding alpha-iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from d- or l-arabinose, and the structures were confirmed by X-ray crystallographic analysis of key intermediates. All compounds were inactive against IDUA, although l-IdoA-configured 8 moderately inhibited beta-glucuronidase (beta-GLU). The d-GlcA-configured 9 was a potent inhibitor of beta-GLU and a moderate inhibitor of the endo-beta-glucuronidase heparanase. Co-crystallization of 9 with heparanase revealed that the endocyclic nitrogen of 9 forms close interactions with both the catalytic acid and catalytic nucleophile. Synthesis of Uronic Acid 1-Azasugars as Putative Inhibitors of alpha-Iduronidase, beta-Glucuronidase and Heparanase.,Doherty GG, Ler GJM, Wimmer N, Bernhardt PV, Ashmus RA, Vocadlo DJ, Armstrong Z, Davies GJ, Maccarana M, Li JP, Kayal Y, Ferro V Chembiochem. 2023 Feb 14;24(4):e202200619. doi: 10.1002/cbic.202200619. Epub 2023 , Jan 3. PMID:36453606 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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