4edy: Difference between revisions

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[[Image:4edy.png|left|200px]]
==Crystal structure of hH-PGDS with water displacing inhibitor==
<StructureSection load='4edy' size='340' side='right' caption='[[4edy]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4edy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EDY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EDY FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9PQ:4-[2-(HYDROXYMETHYL)NAPHTHALEN-1-YL]-N-[2-(MORPHOLIN-4-YL)ETHYL]BENZAMIDE'>9PQ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</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">[[4edz|4edz]], [[4ee0|4ee0]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GSTS, HPGDS, PGDS, PTGDS2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4edy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4edy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4edy RCSB], [http://www.ebi.ac.uk/pdbsum/4edy PDBsum]</span></td></tr>
</table>
== Function ==
[[http://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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.


{{STRUCTURE_4edy|  PDB=4edy  |  SCENE=  }}
Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): A tale of two waters.,Trujillo JI, Kiefer JR, Huang W, Day JE, Moon J, Jerome GM, Bono CP, Kornmeier CM, Williams ML, Kuhn C, Rennie GR, Wynn TA, Carron CP, Thorarensen A Bioorg Med Chem Lett. 2012 Jun 1;22(11):3795-9. Epub 2012 Apr 13. PMID:22546671<ref>PMID:22546671</ref>


===Crystal structure of hH-PGDS with water displacing inhibitor===
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
{{ABSTRACT_PUBMED_22546671}}
 
==About this Structure==
[[4edy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EDY OCA].


==See Also==
==See Also==
*[[Glutathione S-transferase|Glutathione S-transferase]]
*[[Glutathione S-transferase|Glutathione S-transferase]]
 
*[[Prostaglandin D synthase|Prostaglandin D synthase]]
==Reference==
== References ==
<ref group="xtra">PMID:022546671</ref><references group="xtra"/>
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Day, J E.]]
[[Category: Day, J E]]
[[Category: Kiefer, J R.]]
[[Category: Kiefer, J R]]
[[Category: Thorarensen, A.]]
[[Category: Thorarensen, A]]
[[Category: Trujillo, J I.]]
[[Category: Trujillo, J I]]
[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Isomerase-isomerase inhibitor complex]]
[[Category: Isomerase-isomerase inhibitor complex]]
[[Category: Solvent replacement]]
[[Category: Solvent replacement]]

Revision as of 03:30, 25 December 2014

Crystal structure of hH-PGDS with water displacing inhibitorCrystal structure of hH-PGDS with water displacing inhibitor

Structural highlights

4edy is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , ,
Gene:GSTS, HPGDS, PGDS, PTGDS2 (Homo sapiens)
Resources:FirstGlance, OCA, RCSB, PDBsum

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

The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.

Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): A tale of two waters.,Trujillo JI, Kiefer JR, Huang W, Day JE, Moon J, Jerome GM, Bono CP, Kornmeier CM, Williams ML, Kuhn C, Rennie GR, Wynn TA, Carron CP, Thorarensen A Bioorg Med Chem Lett. 2012 Jun 1;22(11):3795-9. Epub 2012 Apr 13. PMID:22546671[9]

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

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ Trujillo JI, Kiefer JR, Huang W, Day JE, Moon J, Jerome GM, Bono CP, Kornmeier CM, Williams ML, Kuhn C, Rennie GR, Wynn TA, Carron CP, Thorarensen A. Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): A tale of two waters. Bioorg Med Chem Lett. 2012 Jun 1;22(11):3795-9. Epub 2012 Apr 13. PMID:22546671 doi:10.1016/j.bmcl.2012.04.004

4edy, resolution 1.72Å

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