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Structural characterization of human heparanase reveals insights into substrate recognition

DOI: 10.1038/nsmb.3136 DOI Help
PMID: 26575439 PMID Help

Authors: Liang Wu (University of York) , Cristina M Viola (University of York) , Andrzej Marek Brzozowski (University of York) , Gideon J Davies (University of York)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 22 , PAGES 1016 - 1022

State: Published (Approved)
Published: November 2015
Diamond Proposal Number(s): 9948

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.

Journal Keywords: Carbohydrates; Glycobiology; Hydrolases; Molecular Biology; X-Ray Crystallography

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 16/12/2015 14:06

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)