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5jap

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Revision as of 06:24, 16 October 2019

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Discovered Through X-Ray Fragment Screening

Structural highlights

5jap 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

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 A from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA) Discovered through X-ray Fragment Screening.,Woolford AJ, Pero JE, Aravapalli S, Berdini V, Coyle JE, Day PJ, Dodson AM, Grondin P, Holding FP, Lee LY, Li P, Manas ES, Marino J Jr, Martin AC, McCleland BW, McMenamin RL, Murray CW, Neipp CE, Page LW, Patel VK, Potvain F, Rich S, Rivero RA, Smith K, Somers DO, Trottet L, Velagaleti R, Williams G, Xie R J Med Chem. 2016 May 20. PMID:27167608^[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, Pero JE, Aravapalli S, Berdini V, Coyle JE, Day PJ, Dodson AM, Grondin P, Holding FP, Lee LY, Li P, Manas ES, Marino J Jr, Martin AC, McCleland BW, McMenamin RL, Murray CW, Neipp CE, Page LW, Patel VK, Potvain F, Rich S, Rivero RA, Smith K, Somers DO, Trottet L, Velagaleti R, Williams G, Xie R. Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA) Discovered through X-ray Fragment Screening. J Med Chem. 2016 May 20. PMID:27167608 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00212

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/5jap"

@@ Line 1: / Line 1: @@
 ==Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>) Discovered Through X-Ray Fragment Screening==
-<StructureSection load='5jap' size='340' side='right' caption='[[5jap]], [[Resolution|resolution]] 2.46&Aring;' scene=''>
+<StructureSection load='5jap' size='340' side='right'caption='[[5jap]], [[Resolution|resolution]] 2.46&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5jap]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JAP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JAP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5jap]] 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=5JAP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JAP FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6HZ:(2,5-DIHYDRO-1H-PYRROL-1-YL)(2,6-DIMETHYL[1,1-BIPHENYL]-3-YL)METHANONE'>6HZ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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=5jap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jap OCA], [http://pdbe.org/5jap PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jap RCSB], [http://www.ebi.ac.uk/pdbsum/5jap PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jap ProSAT]</span></td></tr>
@@ Line 29: / Line 30: @@
 </StructureSection>
 [[Category: 1-alkyl-2-acetylglycerophosphocholine esterase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Day, P J]]
 [[Category: Hydrolase]]
 [[Category: Lipid metabolism]]
 [[Category: Phospholipase]]

5jap

From Proteopedia

Revision as of 06:24, 16 October 2019

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Discovered Through X-Ray Fragment Screening

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox

5jap

From Proteopedia

Revision as of 06:24, 16 October 2019

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered Through X-Ray Fragment Screening

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Discovered Through X-Ray Fragment Screening