5i8p

From Proteopedia

(Difference between revisions)

Revision as of 07:08, 3 June 2020

Crystal structure of LP_PLA2 in complex with novel inhibitor

Structural highlights

5i8p 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:
Related:	5i9i
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

Lipoprotein-associated phospholipase A2 (Lp-PLA2) represents a promising therapeutic target for atherosclerosis and Alzheimer's disease. Here we reported the first crystal structures of Lp-PLA2 bound with reversible inhibitors and the thermodynamic characterization of complexes. High rigidity of Lp-PLA2 structure and similar binding modes of inhibitors with completely different scaffolds are revealed. It not only provides the molecular basis for inhibitory activity but also sheds light on the essential features of Lp-PLA2 recognition with reversible inhibitors.

Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors.,Liu Q, Chen X, Chen W, Yuan X, Su H, Shen J, Xu Y J Med Chem. 2016 May 26;59(10):5115-20. doi: 10.1021/acs.jmedchem.6b00282. Epub, 2016 Apr 26. PMID:27078579^[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
↑ Liu Q, Chen X, Chen W, Yuan X, Su H, Shen J, Xu Y. Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors. J Med Chem. 2016 May 26;59(10):5115-20. doi: 10.1021/acs.jmedchem.6b00282. Epub, 2016 Apr 26. PMID:27078579 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00282

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/5i8p"

@@ Line 1: / Line 1: @@
 ==Crystal structure of LP_PLA2 in complex with novel inhibitor==
-<StructureSection load='5i8p' size='340' side='right' caption='[[5i8p]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
+<StructureSection load='5i8p' size='340' side='right'caption='[[5i8p]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5i8p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5I8P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5i8p]] 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=5I8P OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5I8P FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=VQ7:6-[1,1-BIS(OXIDANYLIDENE)-1,4-THIAZINAN-4-YL]-4-[[4-[4-CHLORANYL-3-(TRIFLUOROMETHYL)PHENOXY]-3,5-BIS(FLUORANYL)PHENYL]METHOXY]-1-METHYL-PYRIMIDIN-2-ONE'>VQ7</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VQ7:6-[1,1-BIS(OXIDANYLIDENE)-1,4-THIAZINAN-4-YL]-4-[[4-[4-CHLORANYL-3-(TRIFLUOROMETHYL)PHENOXY]-3,5-BIS(FLUORANYL)PHENYL]METHOXY]-1-METHYL-PYRIMIDIN-2-ONE'>VQ7</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5i9i|5i9i]]</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=5i8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i8p OCA], [http://pdbe.org/5i8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i8p RCSB], [http://www.ebi.ac.uk/pdbsum/5i8p PDBsum]</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=5i8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i8p OCA], [http://pdbe.org/5i8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i8p RCSB], [http://www.ebi.ac.uk/pdbsum/5i8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i8p ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 5i8p" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phospholipase A2 3D structures|Phospholipase A2 3D structures]]
 == References ==
 <references/>
@@ Line 27: / Line 31: @@
 </StructureSection>
 [[Category: 1-alkyl-2-acetylglycerophosphocholine esterase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Liu, Q F]]
 [[Category: Xu, Y C]]
 [[Category: Hydrolase-hydrolase inhibitor complex]]
 [[Category: Lp_pla2 inhibitor]]

5i8p

From Proteopedia

Revision as of 07:08, 3 June 2020

Crystal structure of LP_PLA2 in complex with novel inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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