9XYL
Human prolyl endopeptidase (PREP) - complex with S17092
This is a non-PDB format compatible entry.
Summary for 9XYL
| Entry DOI | 10.2210/pdb9xyl/pdb |
| Descriptor | Prolyl endopeptidase, {(2S,3aS,7aS)-1-[(1R,2R)-2-phenylcyclopropane-1-carbonyl]octahydro-1H-indol-2-yl}(1,3-thiazolidin-3-yl)methanone, GLYCEROL, ... (7 entities in total) |
| Functional Keywords | inhibitor-bound, peptide cleavage, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 6 |
| Total formula weight | 489315.57 |
| Authors | |
| Primary citation | 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., 2026 Cited by 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: 41512187DOI: 10.1021/acs.jmedchem.5c02680 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.81 Å) |
Structure validation
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