8E08

Crystal structure of HPSE P6 in complex with tetraose pentosan inhibitor

8E08 の概要

• エントリーDOI: 10.2210/pdb8e08/pdb
• 分子名称: Heparanase 50 kDa subunit, Heparanase 8 kDa subunit, 2,3,4-tri-O-sulfo-beta-D-xylopyranose-(1-4)-2,3-di-O-sulfo-beta-D-xylopyranose-(1-4)-2,3-di-O-sulfo-beta-D-xylopyranose-(1-4)-2,3-di-O-sulfo-beta-D-xylopyranose, ... (6 entities in total)
• 機能のキーワード: heparanase, heparan sulfate, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57754.75

構造登録者

Whitefield, C.,Jackson, C.J. (登録日: 2022-08-08, 公開日: 2023-07-12, 最終更新日: 2023-10-25)

主引用文献

Whitefield, C.,Vo, Y.,Schwartz, B.D.,Hepburn, C.,Ahmed, F.H.,Onagi, H.,Banwell, M.G.,Nelms, K.,Malins, L.R.,Jackson, C.J.
Complex Inhibitory Mechanism of Glycomimetics with Heparanase.
Biochemistry, 62:2202-2215, 2023

PubMed Abstract: Heparanase (HPSE) is the only mammalian -β-glucuronidase known to catalyze the degradation of heparan sulfate. Dysfunction of HPSE activity has been linked to several disease states, resulting in HPSE becoming the target of numerous therapeutic programs, yet no drug has passed clinical trials to date. Pentosan polysulfate sodium (PPS) is a heterogeneous, FDA-approved drug for the treatment of interstitial cystitis and a known HPSE inhibitor. However, due to its heterogeneity, characterization of its mechanism of HPSE inhibition is challenging. Here, we show that inhibition of HPSE by PPS is complex, involving multiple overlapping binding events, each influenced by factors such as oligosaccharide length and inhibitor-induced changes in the protein secondary structure. The present work advances our molecular understanding of the inhibition of HPSE and will aid in the development of therapeutics for the treatment of a broad range of pathologies associated with enzyme dysfunction, including cancer, inflammatory disease, and viral infections.

PubMed: 37368361
DOI: 10.1021/acs.biochem.3c00038

実験手法

X-RAY DIFFRACTION (1.93 Å)