8TYG

Plasmodium vivax PMV-WM08 inhibitor complex

これはPDB形式変換不可エントリーです。

8TYG の概要

• エントリーDOI: 10.2210/pdb8tyg/pdb
• 分子名称: Plasmepsin V, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (2E,4aR,7aS)-6-[3-(4-chlorophenyl)pyridin-2-yl]-7a-(2,5-difluorophenyl)-2-imino-3-methyloctahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one, ... (7 entities in total)
• 機能のキーワード: plasmepsinv, inhibitor, hydrolase, hydrolase-inhibitor complex
• 由来する生物種: Plasmodium vivax Sal-1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55754.01

構造登録者

Hodder, A.N.,Scally, S.W.,Cowman, A.F. (登録日: 2023-08-25, 公開日: 2024-08-28, 最終更新日: 2025-06-18)

主引用文献

Hodder, A.N.,Sleebs, B.E.,Adams, G.,Rezazadeh, S.,Ngo, A.,Jarman, K.,Scally, S.,Czabotar, P.,Wang, H.,McCauley, J.A.,Olsen, D.B.,Cowman, A.F.
Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors.
Febs J., 292:2843-2864, 2025

PubMed Abstract: A library of known aspartic protease inhibitors was screened to identify compounds that inhibit plasmepsin V from Plasmodium vivax. This screen revealed compounds with an imino-pyrimidinone-fused pyrrolidine (IPF) scaffold that exhibited sub-micromolar inhibitory activity against plasmepsin V. Further screening of IPF analogs against the related aspartic protease plasmepsin X showed inhibitory activity, while a third aspartic protease, plasmepsin IX, was not significantly inhibited. Modifications to the P1 biaryl region of the IPF scaffold differentially modulated inhibition of both plasmepsin V and X. Notably, analogs with potent plasmepsin X inhibitory activity successfully blocked the growth of Plasmodium falciparum in vitro. X-ray structures of IPF analogs in complex with plasmepsin V provided insights into their binding mode and revealed avenues to further improve IPF potency and selectivity between plasmepsin V and X. This understanding of how these compounds interact with the active sites of plasmepsin V and X will serve as a foundation for the future design of dual inhibitors targeting these proteases.

PubMed: 40035447
DOI: 10.1111/febs.70038

実験手法

X-RAY DIFFRACTION (1.64 Å)