6m07
From Proteopedia
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==Crystal structure of Lp-PLA2 in complex with a novel covalent inhibitor== | ==Crystal structure of Lp-PLA2 in complex with a novel covalent inhibitor== | ||
| - | <StructureSection load='6m07' size='340' side='right'caption='[[6m07]]' scene=''> | + | <StructureSection load='6m07' size='340' side='right'caption='[[6m07]], [[Resolution|resolution]] 2.64Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M07 OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M07 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6M07 FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.64Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BWO:(E)-N-[2-(diethylamino)ethyl]-3-[(2S)-1-methanoylpyrrolidin-2-yl]-3-oxidanyl-N-[[4-[4-(trifluoromethyl)-2-[2,2,2-tris(fluoranyl)ethoxy]phenyl]phenyl]methyl]prop-2-enamide'>BWO</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=6m07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m07 OCA], [https://pdbe.org/6m07 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6m07 RCSB], [https://www.ebi.ac.uk/pdbsum/6m07 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6m07 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases. | ||
| + | |||
| + | Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach.,Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y, Gao J, Liu Y, Zhou H, Huang R, Li M, Shen J, Xu Y J Med Chem. 2020 Jul 9;63(13):7052-7065. doi: 10.1021/acs.jmedchem.0c00372. Epub , 2020 Jun 10. PMID:32459096<ref>PMID:32459096</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6m07" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Crystal structure of Lp-PLA2 in complex with a novel covalent inhibitor
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