5lz8

From Proteopedia

(Difference between revisions)

Revision as of 10:56, 12 August 2020

Fragment-based inhibitors of Lipoprotein associated Phospholipase A2

Structural highlights

5lz8 is a 1 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

Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).,Woolford AJ, Day PJ, Beneton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X J Med Chem. 2016 Dec 8;59(23):10738-10749. Epub 2016 Nov 18. PMID:27933945^[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
↑ Woolford AJ, Day PJ, Beneton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X. Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2). J Med Chem. 2016 Dec 8;59(23):10738-10749. Epub 2016 Nov 18. PMID:27933945 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01427

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5lz8"

@@ Line 1: / Line 1: @@
 ==Fragment-based inhibitors of Lipoprotein associated Phospholipase A2==
-<StructureSection load='5lz8' size='340' side='right' caption='[[5lz8]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
+<StructureSection load='5lz8' size='340' side='right'caption='[[5lz8]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5lz8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LZ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LZ8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5lz8]] is a 1 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=5LZ8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LZ8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7BP:5-[2-[(4~{S})-4-~{TERT}-BUTYL-2-OXIDANYLIDENE-PYRROLIDIN-1-YL]ETHOXY]-2-FLUORANYL-BENZENECARBONITRILE'>7BP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7BP:5-[2-[(4~{S})-4-~{TERT}-BUTYL-2-OXIDANYLIDENE-PYRROLIDIN-1-YL]ETHOXY]-2-FLUORANYL-BENZENECARBONITRILE'>7BP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lz8 OCA], [http://pdbe.org/5lz8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lz8 RCSB], [http://www.ebi.ac.uk/pdbsum/5lz8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lz8 ProSAT]</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=5lz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lz8 OCA], [http://pdbe.org/5lz8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lz8 RCSB], [http://www.ebi.ac.uk/pdbsum/5lz8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lz8 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 </div>
 <div class="pdbe-citations 5lz8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phospholipase A2 3D structures|Phospholipase A2 3D structures]]
 == References ==
 <references/>
@@ Line 26: / Line 30: @@
 </StructureSection>
 [[Category: 1-alkyl-2-acetylglycerophosphocholine esterase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Day, P]]
 [[Category: Woolford, A]]

5lz8

From Proteopedia

Revision as of 10:56, 12 August 2020

Fragment-based inhibitors of Lipoprotein associated Phospholipase A2

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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