View source for 9xyk


==Human prolyl endopeptidase (PREP) - complex with JP-7-1-7==
<StructureSection load='9xyk' size='340' side='right'caption='[[9xyk]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9xyk]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9XYK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9XYK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.73&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CRL:4-chloranyl-1-(2-cyclohexylethyl)-3-methyl-~{N}-(2-oxidanylidene-2-pyrrolidin-1-yl-ethyl)pyrazolo[3,4-b]pyridine-5-carboxamide'>A1CRL</scene>, <scene name='pdbligand=B3P:2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>B3P</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9xyk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9xyk OCA], [https://pdbe.org/9xyk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9xyk RCSB], [https://www.ebi.ac.uk/pdbsum/9xyk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9xyk ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

Structure-Guided Optimization of 4-Chloro-Pyrazolopyridine Analogs for Covalent PREP Inhibition.,Thakur K, Fucci I, Pandian J, Suazo KF, Monteiro DCF, Yoo E J Med Chem. 2026 Jan 22;69(2):1303-1321. doi: 10.1021/acs.jmedchem.5c02680. Epub , 2026 Jan 9. PMID:41512187<ref>PMID:41512187</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9xyk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fucci IJ]]
[[Category: Monteiro DCF]]
[[Category: Pandian J]]
[[Category: Thakur K]]
[[Category: Yoo E]]