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| | ==Crystal structure of hydrolase domain of human soluble epoxide hydrolase complexed with a benzoxazole inhibitor== | | ==Crystal structure of hydrolase domain of human soluble epoxide hydrolase complexed with a benzoxazole inhibitor== |
| - | <StructureSection load='3pdc' size='340' side='right' caption='[[3pdc]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='3pdc' size='340' side='right'caption='[[3pdc]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3pdc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PDC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3PDC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3pdc]] is a 2 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=3PDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PDC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZYI:N-(5-CHLORO-1,3-BENZOXAZOL-2-YL)-2-CYCLOPENTYLACETAMIDE'>ZYI</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1s8o|1s8o]], [[1vj5|1vj5]], [[1zd2|1zd2]], [[3iiy|3iiy]], [[3i28|3i28]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZYI:N-(5-CHLORO-1,3-BENZOXAZOL-2-YL)-2-CYCLOPENTYLACETAMIDE'>ZYI</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPHX2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3pdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pdc OCA], [https://pdbe.org/3pdc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pdc RCSB], [https://www.ebi.ac.uk/pdbsum/3pdc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pdc ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Soluble_epoxide_hydrolase Soluble epoxide hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.10 3.3.2.10] </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=3pdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pdc OCA], [http://pdbe.org/3pdc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3pdc RCSB], [http://www.ebi.ac.uk/pdbsum/3pdc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3pdc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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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| | ==See Also== | | ==See Also== |
| - | *[[Epoxide hydrolase|Epoxide hydrolase]] | + | *[[Epoxide hydrolase 3D structures|Epoxide hydrolase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Soluble epoxide hydrolase]] | + | [[Category: Large Structures]] |
| - | [[Category: Kurumbail, R G]] | + | [[Category: Kurumbail RG]] |
| - | [[Category: Williams, J M]] | + | [[Category: Williams JM]] |
| - | [[Category: Acetylation of lysine]]
| + | |
| - | [[Category: Alpha/beta hydrolase fold]]
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| - | [[Category: Beta barrel]]
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| - | [[Category: Binds mg2+]]
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| - | [[Category: Cytoplasm]]
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| - | [[Category: Epoxide hydrolase]]
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| - | [[Category: Epoxide hydrolase fold]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Hypertension]]
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| - | [[Category: Peroxisome]]
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| Structural highlights
Function
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.[1] [2]
Publication Abstract from PubMed
Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC(50) determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.
Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening.,Xing L, McDonald JJ, Kolodziej SA, Kurumbail RG, Williams JM, Warren CJ, O'Neal JM, Skepner JE, Roberds SL J Med Chem. 2011 Mar 10;54(5):1211-22. Epub 2011 Feb 8. PMID:21302953[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cronin A, Mowbray S, Durk H, Homburg S, Fleming I, Fisslthaler B, Oesch F, Arand M. The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1552-7. Epub 2003 Feb 6. PMID:12574508 doi:10.1073/pnas.0437829100
- ↑ Newman JW, Morisseau C, Harris TR, Hammock BD. The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1558-63. Epub 2003 Feb 6. PMID:12574510 doi:10.1073/pnas.0437724100
- ↑ Xing L, McDonald JJ, Kolodziej SA, Kurumbail RG, Williams JM, Warren CJ, O'Neal JM, Skepner JE, Roberds SL. Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening. J Med Chem. 2011 Mar 10;54(5):1211-22. Epub 2011 Feb 8. PMID:21302953 doi:10.1021/jm101382t
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