6m07

From Proteopedia

(Difference between revisions)

Revision as of 05:59, 20 January 2021

Crystal structure of Lp-PLA2 in complex with a novel covalent inhibitor

Structural highlights

6m07 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	PLA2G7, PAFAH (HUMAN)
Activity:	1-alkyl-2-acetylglycerophosphocholine esterase, with EC number 3.1.1.47
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stafforini DM, Satoh K, Atkinson DL, Tjoelker LW, Eberhardt C, Yoshida H, Imaizumi T, Takamatsu S, Zimmerman GA, McIntyre TM, Gray PW, Prescott SM. Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase. J Clin Invest. 1996 Jun 15;97(12):2784-91. PMID:8675689 doi:10.1172/JCI118733
↑ Yamada Y, Yokota M. Loss of activity of plasma platelet-activating factor acetylhydrolase due to a novel Gln281-->Arg mutation. Biochem Biophys Res Commun. 1997 Jul 30;236(3):772-5. PMID:9245731 doi:S0006-291X(97)97047-9
↑ Hiramoto M, Yoshida H, Imaizumi T, Yoshimizu N, Satoh K. A mutation in plasma platelet-activating factor acetylhydrolase (Val279-->Phe) is a genetic risk factor for stroke. Stroke. 1997 Dec;28(12):2417-20. PMID:9412624
↑ Yamada Y, Ichihara S, Fujimura T, Yokota M. Identification of the G994--> T missense in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men. Metabolism. 1998 Feb;47(2):177-81. PMID:9472966
↑ Yoshida H, Imaizumi T, Fujimoto K, Itaya H, Hiramoto M, Yoshimizu N, Fukushi K, Satoh K. A mutation in plasma platelet-activating factor acetylhydrolase (Val279Phe) is a genetic risk factor for cerebral hemorrhage but not for hypertension. Thromb Haemost. 1998 Sep;80(3):372-5. PMID:9759612
↑ Kruse S, Mao XQ, Heinzmann A, Blattmann S, Roberts MH, Braun S, Gao PS, Forster J, Kuehr J, Hopkin JM, Shirakawa T, Deichmann KA. The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am J Hum Genet. 2000 May;66(5):1522-30. Epub 2000 Mar 24. PMID:10733466 doi:S0002-9297(07)62982-6
↑ Kruse S, Mao XQ, Heinzmann A, Blattmann S, Roberts MH, Braun S, Gao PS, Forster J, Kuehr J, Hopkin JM, Shirakawa T, Deichmann KA. The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am J Hum Genet. 2000 May;66(5):1522-30. Epub 2000 Mar 24. PMID:10733466 doi:S0002-9297(07)62982-6
↑ 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. Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach. J Med Chem. 2020 Jul 9;63(13):7052-7065. doi: 10.1021/acs.jmedchem.0c00372. Epub , 2020 Jun 10. PMID:32459096 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00372

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6m07"

@@ Line 1: / Line 1: @@
 ==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]] 2.64&Aring;' scene=''>
 == 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 [http://proteopedia.org/fgij/fg.htm?mol=6M07 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6m07]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6m07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m07 OCA], [http://pdbe.org/6m07 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6m07 RCSB], [http://www.ebi.ac.uk/pdbsum/6m07 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6m07 ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BWO:(2S)-2-[(E)-3-[2-(diethylamino)ethyl-[[4-[4-(trifluoromethyl)-2-[2,2,2-tris(fluoranyl)ethoxy]phenyl]phenyl]methyl]amino]-1-oxidanyl-3-oxidanylidene-prop-1-enyl]pyrrolidine-1-carboxylic+acid'>BWO</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PLA2G7, PAFAH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://proteopedia.org/fgij/fg.htm?mol=6m07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m07 OCA], [http://pdbe.org/6m07 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6m07 RCSB], [http://www.ebi.ac.uk/pdbsum/6m07 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6m07 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 ==
+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>
+From MEDLINE&reg;/PubMed&reg;, 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__
 </StructureSection>
+[[Category: 1-alkyl-2-acetylglycerophosphocholine esterase]]
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Hu HC]]
+[[Category: Hu, H C]]
-[[Category: Xu YC]]
+[[Category: Xu, Y C]]
+[[Category: Complex structure]]
+[[Category: Covalent inhibitor]]
+[[Category: Hydrolase]]
+[[Category: Lp-pla2]]
+[[Category: Serine phospholipase]]

6m07

From Proteopedia

Revision as of 05:59, 20 January 2021

Crystal structure of Lp-PLA2 in complex with a novel covalent inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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