5mwa

From Proteopedia

(Difference between revisions)

Current revision

human sEH Phosphatase in complex with 3-4-3,4-dichlorophenyl-5-phenyl-1,3-oxazol-2-yl-benzoic-acid

Structural highlights

5mwa is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.55Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain.,Kramer JS, Woltersdorf S, Duflot T, Hiesinger K, Lillich FF, Knoll F, Wittmann SK, Klingler FM, Brunst S, Chaikuad A, Morisseau C, Hammock BD, Buccellati C, Sala A, Rovati GE, Leuillier M, Fraineau S, Rondeaux J, Hernandez-Olmos V, Heering J, Merk D, Pogoryelov D, Steinhilber D, Knapp S, Bellien J, Proschak E J Med Chem. 2019 Sep 26;62(18):8443-8460. doi: 10.1021/acs.jmedchem.9b00445. Epub, 2019 Sep 17. PMID:31436984^[3]

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

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
↑ Kramer JS, Woltersdorf S, Duflot T, Hiesinger K, Lillich FF, Knoll F, Wittmann SK, Klingler FM, Brunst S, Chaikuad A, Morisseau C, Hammock BD, Buccellati C, Sala A, Rovati GE, Leuillier M, Fraineau S, Rondeaux J, Hernandez-Olmos V, Heering J, Merk D, Pogoryelov D, Steinhilber D, Knapp S, Bellien J, Proschak E. Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain. J Med Chem. 2019 Sep 26;62(18):8443-8460. doi: 10.1021/acs.jmedchem.9b00445. Epub, 2019 Sep 17. PMID:31436984 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00445

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='5mwa' size='340' side='right'caption='[[5mwa]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mwa]] is a 1 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=5MWA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MWA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mwa]] 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=5MWA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MWA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8S9:3-[4-(3,4-dichlorophenyl)-5-phenyl-1,3-oxazol-2-yl]benzoic+acid'>8S9</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.55&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8S9:3-[4-(3,4-dichlorophenyl)-5-phenyl-1,3-oxazol-2-yl]benzoic+acid'>8S9</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'>[http://proteopedia.org/fgij/fg.htm?mol=5mwa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mwa OCA], [http://pdbe.org/5mwa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mwa RCSB], [http://www.ebi.ac.uk/pdbsum/5mwa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mwa ProSAT]</span></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=5mwa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mwa OCA], [https://pdbe.org/5mwa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mwa RCSB], [https://www.ebi.ac.uk/pdbsum/5mwa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mwa ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chaikuad, A]]
+[[Category: Chaikuad A]]
-[[Category: Fox, N]]
+[[Category: Fox N]]
-[[Category: Knapp, S]]
+[[Category: Knapp S]]
-[[Category: Kramer, J S]]
+[[Category: Kramer JS]]
-[[Category: Pogoryelov, D]]
+[[Category: Pogoryelov D]]
-[[Category: Proschak, E]]
+[[Category: Proschak E]]
-[[Category: Sorrell, F J]]
+[[Category: Sorrell FJ]]
-[[Category: Complex]]
-[[Category: Human soluble epoxide hydrolase]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor]]
-[[Category: Magnesium]]
-[[Category: Phosphatase]]
-[[Category: Seh]]

5mwa

From Proteopedia

Current revision

human sEH Phosphatase in complex with 3-4-3,4-dichlorophenyl-5-phenyl-1,3-oxazol-2-yl-benzoic-acid

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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