7a7g: Difference between revisions
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==Soluble epoxide hydrolase in complex with TK90== | ==Soluble epoxide hydrolase in complex with TK90== | ||
<StructureSection load='7a7g' size='340' side='right'caption='[[7a7g]]' scene=''> | <StructureSection load='7a7g' size='340' side='right'caption='[[7a7g]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A7G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A7G FirstGlance]. <br> | <table><tr><td colspan='2'>[[7a7g]] 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=7A7G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A7G FirstGlance]. <br> | ||
</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=7a7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a7g OCA], [https://pdbe.org/7a7g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a7g RCSB], [https://www.ebi.ac.uk/pdbsum/7a7g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a7g ProSAT]</span></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]] 2.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TK9:(2~{R})-2-[[4-[[4-methoxy-2-(trifluoromethyl)phenyl]methylcarbamoyl]phenyl]methyl]butanoic+acid'>TK9</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=7a7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a7g OCA], [https://pdbe.org/7a7g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a7g RCSB], [https://www.ebi.ac.uk/pdbsum/7a7g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a7g ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[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 == | |||
The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARgamma agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARgamma agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARgamma modulator RB394 (3) simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of 3. We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARgamma modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS. | |||
Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARgamma Modulator.,Hartmann M, Bibli SI, Tews D, Ni X, Kircher T, Kramer JS, Kilu W, Heering J, Hernandez-Olmos V, Weizel L, Scriba GKE, Krait S, Knapp S, Chaikuad A, Merk D, Fleming I, Fischer-Posovszky P, Proschak E J Med Chem. 2021 Mar 11;64(5):2815-2828. doi: 10.1021/acs.jmedchem.0c02063. Epub , 2021 Feb 23. PMID:33620196<ref>PMID:33620196</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7a7g" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Epoxide hydrolase 3D structures|Epoxide hydrolase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chaikuad A]] | [[Category: Chaikuad A]] | ||
Latest revision as of 15:04, 1 February 2024
Soluble epoxide hydrolase in complex with TK90Soluble epoxide hydrolase in complex with TK90
Structural highlights
FunctionHYES_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 PubMedThe metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARgamma agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARgamma agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARgamma modulator RB394 (3) simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of 3. We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARgamma modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS. Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARgamma Modulator.,Hartmann M, Bibli SI, Tews D, Ni X, Kircher T, Kramer JS, Kilu W, Heering J, Hernandez-Olmos V, Weizel L, Scriba GKE, Krait S, Knapp S, Chaikuad A, Merk D, Fleming I, Fischer-Posovszky P, Proschak E J Med Chem. 2021 Mar 11;64(5):2815-2828. doi: 10.1021/acs.jmedchem.0c02063. Epub , 2021 Feb 23. PMID:33620196[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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