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==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='5jau' size='340' side='right'caption='[[5jau]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5jau]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JAU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6HU:(2S)-3-(3-{[4-(2-AMINOETHOXY)-2,6-DIMETHYL[1,1-BIPHENYL]-3-YL]AMINO}-1H-PYRAZOL-1-YL)-2-METHOXYPROPAN-1-OL'>6HU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5jau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jau OCA], [https://pdbe.org/5jau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jau RCSB], [https://www.ebi.ac.uk/pdbsum/5jau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jau ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PAFA_HUMAN PAFA_HUMAN] Defects in PLA2G7 are the cause of platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:[https://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:[https://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:[https://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 ==
[https://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.
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== 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<ref>PMID:27167608</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5jau" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phospholipase A2 3D structures|Phospholipase A2 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Day PJ]]