7PR8

Crystal structure of human heparanase in complex with covalent inhibitor GR109

Summary for 7PR8

• Entry DOI: 10.2210/pdb7pr8/pdb
• Related: 7PR7
• Descriptor: Heparanase 50 kDa subunit, Heparanase 8 kDa subunit, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: glycoside hydrolase, carbohydrate, glucuronidase, gh79, heparan sulfate
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 53538.67

Authors

Wu, L.,Armstrong, Z.,Davies, G.J. (deposition date: 2021-09-21, release date: 2022-08-03, Last modification date: 2024-10-09)

Primary citation

de Boer, C.,Armstrong, Z.,Lit, V.A.J.,Barash, U.,Ruijgrok, G.,Boyango, I.,Weitzenberg, M.M.,Schroder, S.P.,Sarris, A.J.C.,Meeuwenoord, N.J.,Bule, P.,Kayal, Y.,Ilan, N.,Codee, J.D.C.,Vlodavsky, I.,Overkleeft, H.S.,Davies, G.J.,Wu, L.
Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo.
Proc.Natl.Acad.Sci.USA, 119:e2203167119-e2203167119, 2022

PubMed Abstract: Heparan sulfate proteoglycans (HSPGs) mediate essential interactions throughout the extracellular matrix (ECM), providing signals that regulate cellular growth and development. Altered HSPG composition during tumorigenesis strongly aids cancer progression. Heparanase (HPSE) is the principal enzyme responsible for extracellular heparan sulfate catabolism and is markedly up-regulated in aggressive cancers. HPSE overactivity degrades HSPGs within the ECM, facilitating metastatic dissemination and releasing mitogens that drive cellular proliferation. Reducing extracellular HPSE activity reduces cancer growth, but few effective inhibitors are known, and none are clinically approved. Inspired by the natural glycosidase inhibitor cyclophellitol, we developed nanomolar mechanism-based, irreversible HPSE inhibitors that are effective within physiological environments. Application of cyclophellitol-derived HPSE inhibitors reduces cancer aggression in cellulo and significantly ameliorates murine metastasis. Mechanism-based irreversible HPSE inhibition is an unexplored anticancer strategy. We demonstrate the feasibility of such compounds to control pathological HPSE-driven malignancies.

PubMed: 35881786
DOI: 10.1073/pnas.2203167119

Experimental method

X-RAY DIFFRACTION (1.66 Å)