View source for 3f96


==Crystal structure of human plasma platelet activating factor acetylhydrolase covalently inhibited by sarin==
<StructureSection load='3f96' size='340' side='right'caption='[[3f96]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3f96]] is a 2 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=3F96 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3F96 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]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SGB:O-[(S)-METHYL(1-METHYLETHOXY)PHOSPHORYL]-L-SERINE'>SGB</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=3f96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f96 OCA], [https://pdbe.org/3f96 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3f96 RCSB], [https://www.ebi.ac.uk/pdbsum/3f96 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3f96 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.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f9/3f96_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3f96 ConSurf].
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== Publication Abstract from PubMed ==
The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(R) stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes.,Samanta U, Kirby SD, Srinivasan P, Cerasoli DM, Bahnson BJ Biochem Pharmacol. 2009 Aug 15;78(4):420-9. Epub 2009 Apr 24. PMID:19394314<ref>PMID:19394314</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 3f96" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phospholipase A2 3D structures|Phospholipase A2 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bahnson BJ]]
[[Category: Samanta U]]