5E9C

Crystal structure of human heparanase in complex with heparin tetrasaccharide dp4

Summary for 5E9C

• Entry DOI: 10.2210/pdb5e9c/pdb
• Descriptor: Heparanase, 4-deoxy-2-O-sulfo-alpha-L-threo-hex-4-enopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: glycoside hydrolase, ligand 4, protein, sugar, hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Lysosome membrane; Peripheral membrane protein: Q9Y251 Q9Y251
• Total number of polymer chains: 2
• Total formula weight: 54146.11

Authors

Wu, L.,Davies, G.J. (deposition date: 2015-10-15, release date: 2015-11-18, Last modification date: 2024-11-06)

Primary citation

Wu, L.,Viola, C.M.,Brzozowski, A.M.,Davies, G.J.
Structural characterization of human heparanase reveals insights into substrate recognition.
Nat.Struct.Mol.Biol., 22:1016-1022, 2015

PubMed Abstract: 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.

PubMed: 26575439
DOI: 10.1038/nsmb.3136

Experimental method

X-RAY DIFFRACTION (1.73 Å)