7rg8

Crystal Structure of a Stable Heparanase Mutant

spinqualitylabelsall models 7rg8, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7rg8 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. Method: X-ray diffraction, Resolution 1.3Å Ligands: ACT, NA 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 Heparanase is the only human enzyme known to hydrolyse heparin sulfate and is involved in many important physiological processes. However, it is also unregulated in many disease states, such as cancer, diabetes and Covid-19. It is thus an important drug target, yet the heterologous production of heparanase is challenging and only possible in mammalian or insect expression systems, which limits the ability of many laboratories to study it. Here we describe the computational redesign of heparanase to allow high yield expression in Escherchia coli. This mutated form of heparanase exhibits essentially identical kinetics, inhibition, structure and protein dynamics to the wild type protein, despite the presence of 26 mutations. This variant will facilitate wider study of this important enzyme and contributes to a growing body of literature that shows evolutionarily conserved and functionally neutral mutations can have significant effects on protein folding and expression. Computational design and experimental characterisation of a stable human heparanase variant.,Whitefield C, Hong N, Mitchell JA, Jackson CJ RSC Chem Biol. 2022 Feb 15;3(3):341-349. doi: 10.1039/d1cb00239b. eCollection , 2022 Mar 9. PMID:35382258 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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