1v40

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(New page: 200px<br /> <applet load="1v40" size="450" color="white" frame="true" align="right" spinBox="true" caption="1v40, resolution 1.90&Aring;" /> '''First Inhibitor Com...)
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[[Image:1v40.gif|left|200px]]<br />
 
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<applet load="1v40" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1v40, resolution 1.90&Aring;" />
 
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'''First Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase'''<br />
 
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==Overview==
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==First Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase==
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Hematopoietic prostaglandin (PG) D synthase (H-PGDS) is responsible for, the production of PGD(2) as an allergy or inflammation mediator in mast, and Th2 cells. We determined the X-ray structure of human H-PGDS complexed, with an inhibitor, 2-(2'-benzothiazolyl)-5-styryl-3-(4'-phthalhydrazidyl), tetrazolium chloride (BSPT) at 1.9 A resolution in the presence of Mg(2+)., The styryl group of the inhibitor penetrated to the bottom of the active, site cleft, and the tetrazole ring was stabilized by the stacking, interaction with Trp104, inducing large movement around the alpha5-helix, which caused the space group of the complex crystal to change from P2(1), to P1 upon binding of BSPT. The phthalhydrazidyl group of BSPT exhibited, steric hindrance due to the cofactor, glutathione (GSH), increasing the, IC(50) value of BSPT for human H-PGDS from 36.2 micro M to 98.1 micro M, upon binding of Mg(2+), because the K(m) value of GSH for human H-PGDS was, decreased from 0.60 micro M in the presence of EDTA to 0.14 micro M in the, presence of Mg(2+). We have to avoid steric hindrance of the GSH molecule, that was stabilized by intracellular Mg(2+) in the mM range in the cytosol, for further development of structure-based anti-allergic drugs.
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<StructureSection load='1v40' size='340' side='right'caption='[[1v40]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1v40]] is a 4 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=1V40 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1V40 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=O16:3-(1,3-BENZOTHIAZOL-2-YL)-2-(1,4-DIOXO-1,2,3,4-TETRAHYDROPHTHALAZIN-6-YL)-5-[(E)-2-PHENYLVINYL]-3H-TETRAAZOL-2-IUM'>O16</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1v40 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1v40 OCA], [https://pdbe.org/1v40 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1v40 RCSB], [https://www.ebi.ac.uk/pdbsum/1v40 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1v40 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/HPGDS_HUMAN HPGDS_HUMAN] Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.<ref>PMID:10824118</ref> <ref>PMID:11672424</ref> <ref>PMID:9425264</ref> <ref>PMID:9353279</ref> <ref>PMID:12627223</ref> <ref>PMID:15113825</ref> <ref>PMID:16547010</ref> <ref>PMID:19939518</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/v4/1v40_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1v40 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Hematopoietic prostaglandin (PG) D synthase (H-PGDS) is responsible for the production of PGD(2) as an allergy or inflammation mediator in mast and Th2 cells. We determined the X-ray structure of human H-PGDS complexed with an inhibitor, 2-(2'-benzothiazolyl)-5-styryl-3-(4'-phthalhydrazidyl) tetrazolium chloride (BSPT) at 1.9 A resolution in the presence of Mg(2+). The styryl group of the inhibitor penetrated to the bottom of the active site cleft, and the tetrazole ring was stabilized by the stacking interaction with Trp104, inducing large movement around the alpha5-helix, which caused the space group of the complex crystal to change from P2(1) to P1 upon binding of BSPT. The phthalhydrazidyl group of BSPT exhibited steric hindrance due to the cofactor, glutathione (GSH), increasing the IC(50) value of BSPT for human H-PGDS from 36.2 micro M to 98.1 micro M upon binding of Mg(2+), because the K(m) value of GSH for human H-PGDS was decreased from 0.60 micro M in the presence of EDTA to 0.14 micro M in the presence of Mg(2+). We have to avoid steric hindrance of the GSH molecule that was stabilized by intracellular Mg(2+) in the mM range in the cytosol for further development of structure-based anti-allergic drugs.
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==About this Structure==
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First determination of the inhibitor complex structure of human hematopoietic prostaglandin D synthase.,Inoue T, Okano Y, Kado Y, Aritake K, Irikura D, Uodome N, Okazaki N, Kinugasa S, Shishitani H, Matsumura H, Kai Y, Urade Y J Biochem. 2004 Mar;135(3):279-83. PMID:15113825<ref>PMID:15113825</ref>
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1V40 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, GSH, O16 and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prostaglandin-D_synthase Prostaglandin-D synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.99.2 5.3.99.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1V40 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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First determination of the inhibitor complex structure of human hematopoietic prostaglandin D synthase., Inoue T, Okano Y, Kado Y, Aritake K, Irikura D, Uodome N, Okazaki N, Kinugasa S, Shishitani H, Matsumura H, Kai Y, Urade Y, J Biochem (Tokyo). 2004 Mar;135(3):279-83. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15113825 15113825]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1v40" style="background-color:#fffaf0;"></div>
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[[Category: Prostaglandin-D synthase]]
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[[Category: Single protein]]
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[[Category: Aritake, K.]]
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[[Category: Inoue, T.]]
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[[Category: Irikura, D.]]
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[[Category: Kado, Y.]]
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[[Category: Kai, Y.]]
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[[Category: Kinugasa, S.]]
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[[Category: Matsumura, H.]]
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[[Category: Okano, Y.]]
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[[Category: Okazaki, N.]]
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[[Category: Uodome, N.]]
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[[Category: Urade, Y.]]
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[[Category: GOL]]
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[[Category: GSH]]
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[[Category: MG]]
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[[Category: O16]]
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[[Category: gst]]
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[[Category: hematopoietic prostaglandin d synthase]]
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[[Category: ligase]]
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[[Category: pgds]]
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[[Category: sigma-2 class gst]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:41:12 2007''
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==See Also==
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*[[Glutathione S-transferase 3D structures|Glutathione S-transferase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Aritake K]]
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[[Category: Inoue T]]
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[[Category: Irikura D]]
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[[Category: Kado Y]]
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[[Category: Kai Y]]
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[[Category: Kinugasa S]]
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[[Category: Matsumura H]]
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[[Category: Okano Y]]
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[[Category: Okazaki N]]
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[[Category: Uodome N]]
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[[Category: Urade Y]]

Current revision

First Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase

PDB ID 1v40

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