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5aix

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Revision as of 02:06, 11 March 2017

Complex of human hematopoietic prostagandin D2 synthase (hH-PGDS) in complex with an active site inhibitor.

Structural highlights

5aix is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5ais, 5aiv
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Human H-PGDS has shown promise as a potential target for anti-allergic and anti-inflammatory drugs. Here we describe the discovery of a novel class of indole inhibitors, identified through focused screening of 42,000 compounds and evaluated using a series of hit validation assays that included fluorescence polarization binding, 1D NMR, ITC and chromogenic enzymatic assays. Compounds with low nanomolar potency, favorable physico-chemical properties and inhibitory activity in human mast cells have been identified. In addition, our studies suggest that the active site of hH-PGDS can accommodate larger structural diversity than previously thought, such as the introduction of polar groups in the inner part of the binding pocket.

Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS).,Edfeldt F, Evenas J, Lepisto M, Ward A, Petersen J, Wissler L, Rohman M, Sivars U, Svensson K, Perry M, Feierberg I, Zhou XH, Hansson T, Narjes F Bioorg Med Chem Lett. 2015 Jun 15;25(12):2496-500. doi:, 10.1016/j.bmcl.2015.04.065. Epub 2015 Apr 28. PMID:25978964^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kanaoka Y, Fujimori K, Kikuno R, Sakaguchi Y, Urade Y, Hayaishi O. Structure and chromosomal localization of human and mouse genes for hematopoietic prostaglandin D synthase. Conservation of the ancestral genomic structure of sigma-class glutathione S-transferase. Eur J Biochem. 2000 Jun;267(11):3315-22. PMID:10824118
↑ Jowsey IR, Thomson AM, Flanagan JU, Murdock PR, Moore GB, Meyer DJ, Murphy GJ, Smith SA, Hayes JD. Mammalian class Sigma glutathione S-transferases: catalytic properties and tissue-specific expression of human and rat GSH-dependent prostaglandin D2 synthases. Biochem J. 2001 Nov 1;359(Pt 3):507-16. PMID:11672424
↑ Suzuki T, Watanabe K, Kanaoka Y, Sato T, Hayaishi O. Induction of hematopoietic prostaglandin D synthase in human megakaryocytic cells by phorbol ester. Biochem Biophys Res Commun. 1997 Dec 18;241(2):288-93. PMID:9425264 doi:http://dx.doi.org/10.1006/bbrc.1997.7803
↑ Mahmud I, Ueda N, Yamaguchi H, Yamashita R, Yamamoto S, Kanaoka Y, Urade Y, Hayaishi O. Prostaglandin D synthase in human megakaryoblastic cells. J Biol Chem. 1997 Nov 7;272(45):28263-6. PMID:9353279
↑ Inoue T, Irikura D, Okazaki N, Kinugasa S, Matsumura H, Uodome N, Yamamoto M, Kumasaka T, Miyano M, Kai Y, Urade Y. Mechanism of metal activation of human hematopoietic prostaglandin D synthase. Nat Struct Biol. 2003 Apr;10(4):291-6. PMID:12627223 doi:10.1038/nsb907
↑ Inoue T, Okano Y, Kado Y, Aritake K, Irikura D, Uodome N, Okazaki N, Kinugasa S, Shishitani H, Matsumura H, Kai Y, Urade Y. First determination of the inhibitor complex structure of human hematopoietic prostaglandin D synthase. J Biochem. 2004 Mar;135(3):279-83. PMID:15113825
↑ Aritake K, Kado Y, Inoue T, Miyano M, Urade Y. Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase. J Biol Chem. 2006 Jun 2;281(22):15277-86. Epub 2006 Mar 17. PMID:16547010 doi:10.1074/jbc.M506431200
↑ Weber JE, Oakley AJ, Christ AN, Clark AG, Hayes JD, Hall R, Hume DA, Board PG, Smythe ML, Flanagan JU. Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D2 synthase. Eur J Med Chem. 2010 Feb;45(2):447-54. Epub 2009 Oct 23. PMID:19939518 doi:10.1016/j.ejmech.2009.10.025
↑ Edfeldt F, Evenas J, Lepisto M, Ward A, Petersen J, Wissler L, Rohman M, Sivars U, Svensson K, Perry M, Feierberg I, Zhou XH, Hansson T, Narjes F. Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS). Bioorg Med Chem Lett. 2015 Jun 15;25(12):2496-500. doi:, 10.1016/j.bmcl.2015.04.065. Epub 2015 Apr 28. PMID:25978964 doi:http://dx.doi.org/10.1016/j.bmcl.2015.04.065

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5aix"

@@ Line 1: / Line 1: @@
 ==Complex of human hematopoietic prostagandin D2 synthase (hH-PGDS) in complex with an active site inhibitor.==
 <StructureSection load='5aix' size='340' side='right' caption='[[5aix]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=KRX:6-(3-METHOXYPHENYL)-N-[1-(2,2,2-TRIFLUOROETHYL)PIPERIDIN-4-YL]PYRIDINE-3-CARBOXAMIDE'>KRX</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ais|5ais]], [[5aiv|5aiv]]</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=5aix FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aix OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5aix RCSB], [http://www.ebi.ac.uk/pdbsum/5aix PDBsum]</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=5aix FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aix OCA], [http://pdbe.org/5aix PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aix RCSB], [http://www.ebi.ac.uk/pdbsum/5aix PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5aix ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 5aix" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

5aix

From Proteopedia

Revision as of 02:06, 11 March 2017

Complex of human hematopoietic prostagandin D2 synthase (hH-PGDS) in complex with an active site inhibitor.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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