4y2v: Difference between revisions
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<StructureSection load='4y2v' size='340' side='right'caption='[[4y2v]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='4y2v' size='340' side='right'caption='[[4y2v]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4y2v]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4y2v]] is a 1 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=4Y2V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y2V FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4A5:(4-BROMO-3-CYCLOPROPYL-1H-PYRAZOL-1-YL)ACETIC+ACID'>4A5</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4A5:(4-BROMO-3-CYCLOPROPYL-1H-PYRAZOL-1-YL)ACETIC+ACID'>4A5</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=4y2v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y2v OCA], [https://pdbe.org/4y2v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y2v RCSB], [https://www.ebi.ac.uk/pdbsum/4y2v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y2v ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/HYES_HUMAN HYES_HUMAN] Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate.<ref>PMID:12574508</ref> <ref>PMID:12574510</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Amano Y]] | |||
[[Category: Amano | [[Category: Yamaguchi T]] | ||
[[Category: Yamaguchi | |||
Revision as of 21:04, 26 April 2023
Structure of soluble epoxide hydrolase in complex with (4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)acetic acidStructure of soluble epoxide hydrolase in complex with (4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)acetic acid
Structural highlights
FunctionHYES_HUMAN Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate.[1] [2] Publication Abstract from PubMedSoluble epoxide hydrolase (sEH) is a potential target for the treatment of inflammation and hypertension. X-ray crystallographic fragment screening was used to identify fragment hits and their binding modes. Eight fragment hits were identified via soaking of sEH crystals with fragment cocktails, and the co-crystal structures of these hits were determined via individual soaking. Based on the binding mode, N-ethylmethylamine was identified as a promising scaffold that forms hydrogen bonds with the catalytic residues of sEH, Asp335, Tyr383, and Tyr466. Compounds containing this scaffold were selected from an in-house chemical library and assayed. Although the starting fragment had a weak inhibitory activity (IC50: 800muM), we identified potent inhibitors including 2-({[2-(adamantan-1-yl)ethyl]amino}methyl)phenol exhibiting the highest inhibitory activity (IC50: 0.51muM). This corresponded to a more than 1500-fold increase in inhibitory activity compared to the starting fragment. Co-crystal structures of the hit compounds demonstrate that the binding of N-ethylmethylamine to catalytic residues is similar to that of the starting fragment. We therefore consider crystallographic fragment screening to be appropriate for the identification of weak but promising fragment hits. Identification of N-ethylmethylamine as a novel scaffold for inhibitors of soluble epoxide hydrolase by crystallographic fragment screening.,Amano Y, Tanabe E, Yamaguchi T Bioorg Med Chem. 2015 May 15;23(10):2310-7. doi: 10.1016/j.bmc.2015.03.083. Epub , 2015 Apr 6. PMID:25862210[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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