5yea
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | The | + | ==The crystal structure of Lp-PLA2 in complex with a novel inhibitor== |
| + | <StructureSection load='5yea' size='340' side='right' caption='[[5yea]], [[Resolution|resolution]] 1.81Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5yea]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YEA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YEA FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8U9:4-[[4-[4-chloranyl-3-(trifluoromethyl)phenoxy]-3-cyano-phenyl]sulfamoyl]benzoic+acid'>8U9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/1-alkyl-2-acetylglycerophosphocholine_esterase 1-alkyl-2-acetylglycerophosphocholine esterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.47 3.1.1.47] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5yea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yea OCA], [http://pdbe.org/5yea PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yea RCSB], [http://www.ebi.ac.uk/pdbsum/5yea PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yea ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/PAFA_HUMAN PAFA_HUMAN]] Defects in PLA2G7 are the cause of platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:[http://omim.org/entry/614278 614278]]. An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. Asthmatic individuals affected by this condition may manifest severe respiratory symptoms.<ref>PMID:8675689</ref> <ref>PMID:9245731</ref> <ref>PMID:9412624</ref> <ref>PMID:9472966</ref> <ref>PMID:9759612</ref> Defects in PLA2G7 are a cause of susceptibility to asthma (ASTHMA) [MIM:[http://omim.org/entry/600807 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.<ref>PMID:10733466</ref> Defects in PLA2G7 are a cause of susceptibility to atopic hypersensitivity (ATOPY) [MIM:[http://omim.org/entry/147050 147050]]. A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma.<ref>PMID:10733466</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PAFA_HUMAN 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. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design. | ||
| - | + | Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.,Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y J Med Chem. 2017 Dec 28;60(24):10231-10244. doi: 10.1021/acs.jmedchem.7b01530., Epub 2017 Dec 15. PMID:29193967<ref>PMID:29193967</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Liu, Q | + | <div class="pdbe-citations 5yea" style="background-color:#fffaf0;"></div> |
| - | [[Category: Xu, Y | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: 1-alkyl-2-acetylglycerophosphocholine esterase]] | ||
| + | [[Category: Liu, Q F]] | ||
| + | [[Category: Xu, Y C]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Hydrolase inhibitor]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 07:10, 25 July 2018
The crystal structure of Lp-PLA2 in complex with a novel inhibitor
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