4od0: Difference between revisions

Revision as of 08:58, 10 April 2019

Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea

Structural highlights

4od0 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	2RV, MG, PO4
Related:	4ocz
Gene:	EPHX2 (HUMAN)
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:https://dx.doi.org/10.1021/jm500694p

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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:https://dx.doi.org/10.1021/jm500694p

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
 ==Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea==
-<StructureSection load='4od0' size='340' side='right' caption='[[4od0]], [[Resolution|resolution]] 2.92&Aring;' scene=''>
+<StructureSection load='4od0' size='340' side='right'caption='[[4od0]], [[Resolution|resolution]] 2.92&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4od0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OD0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OD0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4od0]] 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=4OD0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OD0 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2RV:1-(1-PROPANOYLPIPERIDIN-4-YL)-3-[4-(TRIFLUOROMETHOXY)PHENYL]UREA'>2RV</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ocz|4ocz]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4od0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4od0 OCA], [http://pdbe.org/4od0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4od0 RCSB], [http://www.ebi.ac.uk/pdbsum/4od0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4od0 ProSAT]</span></td></tr>
 </table>
@@ Line 26: / Line 27: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Dong, H]]
 [[Category: Eldin, M L]]

4od0: Difference between revisions

Revision as of 08:58, 10 April 2019

Crystal structure of human soluble epoxide hydrolase complexed with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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