Curtin University Homepage
  • Library
  • Help
    • Admin

    espace - Curtin’s institutional repository

    JavaScript is disabled for your browser. Some features of this site may not work without it.
    View Item 
    • espace Home
    • espace
    • Curtin Research Publications
    • View Item
    • espace Home
    • espace
    • Curtin Research Publications
    • View Item

    Computational analyses of the catalytic and heparin binding sites and their interactions with glycosaminoglycans in glycoside hydrolase family 79 endo-β-D-glucuronidase (heparanase)

    Access Status
    Open access via publisher
    Authors
    Gandhi, Neha
    Freeman, C.
    Parish, C.
    Mancera, Ricardo
    Date
    2012
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Gandhi, N. and Freeman, C. and Parish, C. and Mancera, R. 2012. Computational analyses of the catalytic and heparin binding sites and their interactions with glycosaminoglycans in glycoside hydrolase family 79 endo-β-D-glucuronidase (heparanase). Glycobiology. 22 (1): pp. 35-55.
    Source Title
    Glycobiology
    DOI
    10.1093/glycob/cwr095
    ISSN
    09596658
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/30588
    Collection
    • Curtin Research Publications
    Abstract

    Mammalian heparanase is an endo-β-glucuronidase associated with cell invasion in cancer metastasis, angiogenesis and inflammation. Heparanase cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, releasing heparin/heparan sulfate oligosaccharides of appreciable size. This in turn causes the release of growth factors, which accelerate tumor growth and metastasis. Heparanase has two glycosaminoglycan-binding domains; however, no three-dimensional structure information is available for human heparanase that can provide insights into how the two domains interact to degrade heparin fragments. We have constructed a new homology model of heparanase that takes into account the most recent structural and bioinformatics data available. Heparin analogs and glycosaminoglycan mimetics were computationally docked into the active site with energetically stable ring conformations and their interaction energies were compared. The resulting docked structures were used to propose a model for substrates and conformer selectivity based on the dimensions of the active site. The docking of substrates and inhibitors indicates the existence of a large binding site extending at least two saccharide units beyond the cleavage site (toward the nonreducing end) and at least three saccharides toward the reducing end (toward heparin-binding site 2). The docking of substrates suggests that heparanase recognizes the N-sulfated and O-sulfated glucosamines at subsite +1 and glucuronic acid at the cleavage site, whereas in the absence of 6-O-sulfation in glucosamine, glucuronic acid is docked at subsite +2. These findings will help us to focus on the rational design of heparanase-inhibiting molecules for anticancer drug development by targeting the two heparin/heparan sulfate recognition domains.

    Related items

    Showing items related by title, author, creator and subject.

    • Molecular modelling of platelet endothelial cell adhesion molecule 1 and its interaction with glycosaminoglycans
      Gandhi, Neha Sureshchandra (2007)
      The Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) has many functions including its roles in leukocyte extravasation as part of the inflammatory response, and in the maintenance of vascular integrity through its ...
    • Molecular modelling of the interactions of complex carbohydrates with proteins
      Gandhi, Neha Sureshchandra (2011)
      Glycosaminoglycans (GAGs) are ubiquitous complex carbohydrate molecules present on the cell surfaces and in extracellular matrices (ECM) of vertebrate and invertebrate tissues. The interactions of sulphated GAGs such as ...
    • The interaction of heparin tetrasaccharides with chemokine CCL5 is modulated by sulfation pattern and pH
      Singh, A.; Kett, W.; Severin, I.; Agyekum, I.; Duan, J.; Amster, I.; Proudfoot, A.; Coombe, Deidre; Woods, R. (2015)
      © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Interactions between chemokines such as CCL5 and glycosaminoglycans (GAGs) are essential for creating haptotactic gradients to guide the migration ...
    Advanced search

    Browse

    Communities & CollectionsIssue DateAuthorTitleSubjectDocument TypeThis CollectionIssue DateAuthorTitleSubjectDocument Type

    My Account

    Admin

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Follow Curtin

    • 
    • 
    • 
    • 
    • 

    CRICOS Provider Code: 00301JABN: 99 143 842 569TEQSA: PRV12158

    Copyright | Disclaimer | Privacy statement | Accessibility

    Curtin would like to pay respect to the Aboriginal and Torres Strait Islander members of our community by acknowledging the traditional owners of the land on which the Perth campus is located, the Whadjuk people of the Nyungar Nation; and on our Kalgoorlie campus, the Wongutha people of the North-Eastern Goldfields.