8B0C

Crystal structure of human heparanase in complex with covalent inhibitor VB158

これはPDB形式変換不可エントリーです。

8B0C の概要

• エントリーDOI: 10.2210/pdb8b0c/pdb
• 分子名称: Heparanase 50 kDa subunit, Heparanase 8 kDa subunit, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: heparanase, 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: 52603.28

構造登録者

Armstrong, Z.,Davies, G. (登録日: 2022-09-07, 公開日: 2022-12-28, 最終更新日: 2024-11-20)

主引用文献

Borlandelli, V.,Armstrong, Z.,Nin-Hill, A.,Codee, J.D.C.,Raich, L.,Artola, M.,Rovira, C.,Davies, G.J.,Overkleeft, H.S.
4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors.
Chemmedchem, 18:e202200580-e202200580, 2023

PubMed Abstract: Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with β-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over β-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs.

PubMed: 36533564
DOI: 10.1002/cmdc.202200580

実験手法

X-RAY DIFFRACTION (2.1 Å)