6hgx: Difference between revisions

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'''Unreleased structure'''


The entry 6hgx is ON HOLD
==Soluble epoxide hydrolase in complex with 1-(4-((4-(tert-butyl)morpholin-2-yl)methoxy)phenyl)-3-cyclohexylurea==
<StructureSection load='6hgx' size='340' side='right'caption='[[6hgx]], [[Resolution|resolution]] 2.16&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hgx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HGX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HGX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G3T:1-[4-[[(2~{S})-4-~{tert}-butylmorpholin-2-yl]methoxy]phenyl]-3-cyclohexyl-urea'>G3T</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6hgv|6hgv]]</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=6hgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hgx OCA], [http://pdbe.org/6hgx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hgx RCSB], [http://www.ebi.ac.uk/pdbsum/6hgx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hgx 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure analysis of the sEH in complex with talinolol enables a straightforward optimization of inhibitory potency. The resulting lead structure exhibited in vivo activity in a rat model of diabetic neuropatic pain.


Authors: Kramer, J.S., Pogoryelov, D., Hiesinger, K., Proschak, E.
Computer-Aided Selective Optimization of Side Activities of Talinolol.,Hiesinger K, Kramer JS, Achenbach J, Moser D, Weber J, Wittmann SK, Morisseau C, Angioni C, Geisslinger G, Kahnt AS, Kaiser A, Proschak A, Steinhilber D, Pogoryelov D, Wagner K, Hammock BD, Proschak E ACS Med Chem Lett. 2019 May 29;10(6):899-903. doi:, 10.1021/acsmedchemlett.9b00075. eCollection 2019 Jun 13. PMID:31223445<ref>PMID:31223445</ref>


Description: Soluble epoxide hydrolase in complex with 1-(4-((4-(tert-butyl)morpholin-2-yl)methoxy)phenyl)-3-cyclohexylurea
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Proschak, E]]
<div class="pdbe-citations 6hgx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Hiesinger, K]]
[[Category: Hiesinger, K]]
[[Category: Kramer, J S]]
[[Category: Pogoryelov, D]]
[[Category: Pogoryelov, D]]
[[Category: Kramer, J.S]]
[[Category: Proschak, E]]
[[Category: Complex]]
[[Category: Hydrolase]]
[[Category: Inhibitor]]
[[Category: Seh]]

Latest revision as of 08:47, 3 July 2019

Soluble epoxide hydrolase in complex with 1-(4-((4-(tert-butyl)morpholin-2-yl)methoxy)phenyl)-3-cyclohexylureaSoluble epoxide hydrolase in complex with 1-(4-((4-(tert-butyl)morpholin-2-yl)methoxy)phenyl)-3-cyclohexylurea

Structural highlights

6hgx is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure analysis of the sEH in complex with talinolol enables a straightforward optimization of inhibitory potency. The resulting lead structure exhibited in vivo activity in a rat model of diabetic neuropatic pain.

Computer-Aided Selective Optimization of Side Activities of Talinolol.,Hiesinger K, Kramer JS, Achenbach J, Moser D, Weber J, Wittmann SK, Morisseau C, Angioni C, Geisslinger G, Kahnt AS, Kaiser A, Proschak A, Steinhilber D, Pogoryelov D, Wagner K, Hammock BD, Proschak E ACS Med Chem Lett. 2019 May 29;10(6):899-903. doi:, 10.1021/acsmedchemlett.9b00075. eCollection 2019 Jun 13. PMID:31223445[3]

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

References

  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. ↑ Hiesinger K, Kramer JS, Achenbach J, Moser D, Weber J, Wittmann SK, Morisseau C, Angioni C, Geisslinger G, Kahnt AS, Kaiser A, Proschak A, Steinhilber D, Pogoryelov D, Wagner K, Hammock BD, Proschak E. Computer-Aided Selective Optimization of Side Activities of Talinolol. ACS Med Chem Lett. 2019 May 29;10(6):899-903. doi:, 10.1021/acsmedchemlett.9b00075. eCollection 2019 Jun 13. PMID:31223445 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00075

6hgx, resolution 2.16Å

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