6m06 | pdb_00006m06
Crystal structure of Lp-PLA2 in complex with a novel covalent inhibitor
Structural highlights
Disease[PAFA_HUMAN] Defects in PLA2G7 are the cause of platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:614278]. An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. Asthmatic individuals affected by this condition may manifest severe respiratory symptoms.[1] [2] [3] [4] [5] Defects in PLA2G7 are a cause of susceptibility to asthma (ASTHMA) [MIM:600807]. The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with weezing due to spasmodic contraction of the bronchi. Note=PLA2G7 variants can be a risk factor for the development of asthma and PLA2G7 may act as a modifier gene that modulates the severity of this disease.[6] Defects in PLA2G7 are a cause of susceptibility to atopic hypersensitivity (ATOPY) [MIM:147050]. A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma.[7] Function[PAFA_HUMAN] Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF. Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids. Publication Abstract from PubMedCovalent 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[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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