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-β-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-Å to 1.9-Å 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.
