7YI7

Crystal structure of Human HPSE1 in complex with inhibitor

7YI7 の概要

• エントリーDOI: 10.2210/pdb7yi7/pdb
• 分子名称: Heparanase 50 kDa subunit, Heparanase 8 kDa subunit, (5~{S},6~{R},7~{S},8~{S})-6,7,8-tris(oxidanyl)-2-[2-[4-(trifluoromethyl)phenyl]ethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: endo-glucoronidase, heparanase-1, hep, hpa, hpa1, hpr1, hpse1, hse1, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 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: 52123.91

構造登録者

Mima, M.,Fujimoto, N.,Imai, Y. (登録日: 2022-07-15, 公開日: 2022-12-07, 最終更新日: 2024-10-23)

主引用文献

Imai, Y.,Wakasugi, D.,Suzuki, R.,Kato, S.,Sugisaki, M.,Mima, M.,Miyagawa, H.,Endo, M.,Fujimoto, N.,Fukunaga, T.,Kato, S.,Kuroda, S.,Takahashi, T.,Kakinuma, H.
Lead identification of novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent heparanase-1 inhibitor.
Bioorg.Med.Chem.Lett., 79:129050-129050, 2022

PubMed Abstract: Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that cleaves heparan sulfate proteoglycans into short-chain heparan sulfates (HS). The inhibition of HPSE1 has therapeutic potential for proteinuric diseases such as nephrotic syndrome because increased HPSE1 expression is associated with the loss of HS in the glomerular basement membrane, leading to the development of proteinuria. The present study examined the generation of a lead compound focusing on chemical structures with a sugar moiety, such as glycosides and sugar analogs, taking their physical properties into consideration. Compound 10, an exo-β-d-glucuronidase (GUSβ) inhibitor, was found to have a weak inhibitory activity against endo-β-d-glucuronidase HPSE1. A structure-activity relationship study using the X-ray co-crystal structure of 10 and HPSE1 resulted in 12a, which showed a more than 14-fold increase in HPSE1 inhibitory activity compared with that of 10. Compound 12a could be a novel lead compound for the development of a potent HPSE1 inhibitor.

PubMed: 36368497
DOI: 10.1016/j.bmcl.2022.129050

実験手法

X-RAY DIFFRACTION (2.8 Å)