5MWA
human sEH Phosphatase in complex with 3-4-3,4-dichlorophenyl-5-phenyl-1,3-oxazol-2-yl-benzoic-acid
Summary for 5MWA
| Entry DOI | 10.2210/pdb5mwa/pdb |
| Descriptor | Bifunctional epoxide hydrolase 2, MAGNESIUM ION, 3-[4-(3,4-dichlorophenyl)-5-phenyl-1,3-oxazol-2-yl]benzoic acid, ... (4 entities in total) |
| Functional Keywords | phosphatase, complex, inhibitor, magnesium, human soluble epoxide hydrolase, seh, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27835.41 |
| Authors | Kramer, J.S.,Pogoryelov, D.,Sorrell, F.J.,Fox, N.,Chaikuad, A.,Knapp, S.,Proschak, E. (deposition date: 2017-01-18, release date: 2018-02-28, Last modification date: 2024-01-17) |
| Primary citation | Kramer, J.S.,Woltersdorf, S.,Duflot, T.,Hiesinger, K.,Lillich, F.F.,Knoll, F.,Wittmann, S.K.,Klingler, F.M.,Brunst, S.,Chaikuad, A.,Morisseau, C.,Hammock, B.D.,Buccellati, C.,Sala, A.,Rovati, G.E.,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 first in vivo active inhibitors of soluble epoxide hydrolase (sEH) phosphatase domain. J.Med.Chem., 2019 Cited by PubMed Abstract: 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 (, 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. PubMed: 31436984DOI: 10.1021/acs.jmedchem.9b00445 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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