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4ocz

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Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea

Structural highlights

4ocz 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 2.94Å
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

Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.

Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.,Lee KS, Liu JY, Wagner KM, Pakhomova S, Dong H, Morisseau C, Fu SH, Yang J, Wang P, Ulu A, Mate CA, Nguyen LV, Hwang SH, Edin ML, Mara AA, Wulff H, Newcomer ME, Zeldin DC, Hammock BD J Med Chem. 2014 Aug 28;57(16):7016-30. doi: 10.1021/jm500694p. Epub 2014 Aug 11. PMID:25079952^[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
↑ Lee KS, Liu JY, Wagner KM, Pakhomova S, Dong H, Morisseau C, Fu SH, Yang J, Wang P, Ulu A, Mate CA, Nguyen LV, Hwang SH, Edin ML, Mara AA, Wulff H, Newcomer ME, Zeldin DC, Hammock BD. Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy. J Med Chem. 2014 Aug 28;57(16):7016-30. doi: 10.1021/jm500694p. Epub 2014 Aug 11. PMID:25079952 doi:http://dx.doi.org/10.1021/jm500694p

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/4ocz"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4ocz]] 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=4OCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OCZ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2RU:1-[1-(2-METHYLPROPANOYL)PIPERIDIN-4-YL]-3-[4-(TRIFLUOROMETHYL)PHENYL]UREA'>2RU</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.94&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2RU:1-[1-(2-METHYLPROPANOYL)PIPERIDIN-4-YL]-3-[4-(TRIFLUOROMETHYL)PHENYL]UREA'>2RU</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=4ocz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ocz OCA], [https://pdbe.org/4ocz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ocz RCSB], [https://www.ebi.ac.uk/pdbsum/4ocz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ocz ProSAT]</span></td></tr>
 </table>

4ocz

From Proteopedia

Current revision

Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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