5e98 | pdb_00005e98

Crystal structure of human heparanase in complex with HepMer M04S02a

spinqualitylabelsall models 5e98, resolution 1.63Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5e98 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BDP, CL, GNS, NAG, NPO Activity: Heparanase, with EC number 3.2.1.166 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum 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 Heparan sulfate (HS) is a glycosaminoglycan that forms a key component of the extracellular matrix (ECM). Breakdown of HS is carried out by heparanase (HPSE), an endo-beta-glucuronidase of the glycoside hydrolase 79 (GH79) family. Overexpression of HPSE results in breakdown of extracellular HS and release of stored growth factors and hence is strongly linked to cancer metastasis. Here we present crystal structures of human HPSE at 1.6-A to 1.9-A resolution that reveal how an endo-acting binding cleft is exposed by proteolytic activation of latent proHPSE. We used oligosaccharide complexes to map the substrate-binding and sulfate-recognition motifs. These data shed light on the structure and interactions of a key enzyme involved in ECM maintenance and provide a starting point for the design of HPSE inhibitors for use as biochemical tools and anticancer therapeutics. Structural characterization of human heparanase reveals insights into substrate recognition.,Wu L, Viola CM, Brzozowski AM, Davies GJ Nat Struct Mol Biol. 2015 Nov 16. doi: 10.1038/nsmb.3136. PMID:26575439 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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