9Q66

Human prolyl endopeptidase (PREP) - complex with JP-4-1-7

これはPDB形式変換不可エントリーです。

9Q66 の概要

• エントリーDOI: 10.2210/pdb9q66/pdb
• 分子名称: Prolyl endopeptidase, 4-chloro-1-(cyclohexylmethyl)-3-methyl-N-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, 2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (6 entities in total)
• 機能のキーワード: inhibitor-bound, peptide cleavage, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 244999.36

構造登録者

Fucci, I.J.,Thakur, K.,Pandian, J.,Yoo, E.,Monteiro, D.C.F. (登録日: 2025-08-21, 公開日: 2026-01-21, 最終更新日: 2026-02-04)

主引用文献

Thakur, K.,Fucci, I.,Pandian, J.,Suazo, K.F.,Monteiro, D.C.F.,Yoo, E.
Structure-Guided Optimization of 4-Chloro-Pyrazolopyridine Analogs for Covalent PREP Inhibition.
J.Med.Chem., 69:1303-1321, 2026

PubMed Abstract: Prolyl endopeptidase (PREP) is a dynamic serine protease that cleaves proline-containing peptides. PREP is also involved in numerous pathophysiological processes through modulation of protein-protein interactions and has been extensively studied in neurodegenerative diseases. In this study, we report the structure-based design and synthesis of covalent PREP inhibitors built on a 4-chloro-pyrazolopyridine (CPzP) scaffold, previously identified through chemoproteomic screening to target a noncatalytic cysteine residue within the active site. Guided by crystallographic data and molecular docking studies, we optimized initial hits to develop a potent inhibitor exhibiting nanomolar potency in both biochemical and cellular assays, with high selectivity over related serine proteases FAP and DPP4. Molecular dynamics simulations indicated that modulation of the conformational flexibility of a dynamic A-loop within PREP by CPzP analogs may contribute to inhibitory potency. Collectively, this work introduces a new class of structurally distinct inhibitors and provides tools to explore the diverse biological roles of PREP.

PubMed: 41512187
DOI: 10.1021/acs.jmedchem.5c02680

実験手法

X-RAY DIFFRACTION (2.01 Å)