7PR9
Crystal structure of Burkholderia pseudomallei heparanase in complex with covalent inhibitor VL166
Summary for 7PR9
| Entry DOI | 10.2210/pdb7pr9/pdb |
| Related | 7PR7 |
| Descriptor | Glyco_hydro_44 domain-containing protein, 2-acetamido-2-deoxy-alpha-D-glucopyranose-(1-4)-(2R,3S,5R,6R)-2,3,4,5,6-pentakis(oxidanyl)cyclohexane-1-carboxylic acid, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | glycoside hydrolase, carbohydrate, glucuronidase, gh79, hydrolase |
| Biological source | Burkholderia pseudomallei (strain K96243) |
| Total number of polymer chains | 2 |
| Total formula weight | 90472.30 |
| 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 Cited by 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: 35881786DOI: 10.1073/pnas.2203167119 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.34 Å) |
Structure validation
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