2vd1: Difference between revisions
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==Complex structure of prostaglandin D2 synthase at 2.25A.== | |||
<StructureSection load='2vd1' size='340' side='right'caption='[[2vd1]], [[Resolution|resolution]] 2.25Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vd1]] 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=2VD1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VD1 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]] 2.25Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D28:4-{[4-(4-FLUORO-3-METHYLPHENYL)-1,3-THIAZOL-2-YL]AMINO}-2-HYDROXYBENZOIC+ACID'>D28</scene>, <scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=2vd1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vd1 OCA], [https://pdbe.org/2vd1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vd1 RCSB], [https://www.ebi.ac.uk/pdbsum/2vd1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vd1 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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> | |||
== 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/vd/2vd1_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=2vd1 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We describe the discovery of novel inhibitors of prostaglandin D2 synthase (PGDS) through fragment-based lead generation and structure-based drug design. A library of 2500 low-molecular-weight compounds was screened using 2D nuclear magnetic resonance (NMR), leading to the identification of 24 primary hits. Structure determination of protein-ligand complexes with the hits enabled a hit optimization process, whereby we harvested increasingly more potent inhibitors out of our corporate compound collection. Two iterative cycles were carried out, comprising NMR screening, molecular modeling, X-ray crystallography, and in vitro biochemical testing. Six novel high-resolution PGDS complex structures were determined, and 300 hit analogues were tested. This rational drug design procedure culminated in the discovery of 24 compounds with an IC 50 below 1 microM in the in vitro assay. The best inhibitor (IC 50 = 21 nM) is one of the most potent inhibitors of PGDS to date. As such, it may enable new functional in vivo studies of PGDS and the prostaglandin metabolism pathway. | |||
Novel prostaglandin d synthase inhibitors generated by fragment-based drug design.,Hohwy M, Spadola L, Lundquist B, Hawtin P, Dahmen J, Groth-Clausen I, Nilsson E, Persdotter S, von Wachenfeldt K, Folmer RH, Edman K J Med Chem. 2008 Apr 10;51(7):2178-86. Epub 2008 Mar 15. PMID:18341273<ref>PMID:18341273</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2vd1" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[ | *[[Glutathione S-transferase 3D structures|Glutathione S-transferase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Dahmen | [[Category: Dahmen J]] | ||
[[Category: Edman | [[Category: Edman K]] | ||
[[Category: Folmer | [[Category: Folmer RHA]] | ||
[[Category: Groth-Clausen | [[Category: Groth-Clausen I]] | ||
[[Category: Hawtin | [[Category: Hawtin P]] | ||
[[Category: Hohwy | [[Category: Hohwy M]] | ||
[[Category: Lundquist | [[Category: Lundquist B]] | ||
[[Category: Persdotter | [[Category: Persdotter S]] | ||
[[Category: Spadola | [[Category: Spadola L]] | ||
[[Category: Wachenfeldt | [[Category: Von Wachenfeldt K]] | ||
Latest revision as of 15:15, 13 December 2023
Complex structure of prostaglandin D2 synthase at 2.25A.
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