4k1l

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{{STRUCTURE_4k1l| PDB=4k1l | SCENE= }}
 
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===4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 beta-HSD1 inhibitors for the treatment of diabetes===
 
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{{ABSTRACT_PUBMED_23845218}}
 
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==Disease==
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==4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 beta-HSD1 inhibitors for the treatment of diabetes==
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[[http://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN]] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:[http://omim.org/entry/604931 604931]]. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS).
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<StructureSection load='4k1l' size='340' side='right'caption='[[4k1l]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4k1l]] is a 4 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=4K1L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K1L FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.96&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SFF:(4AS,8AR)-N-CYCLOHEXYL-4A,5,6,7,8,8A-HEXAHYDRO-4,1,2-BENZOXATHIAZIN-3-AMINE+1,1-DIOXIDE'>SFF</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4k1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k1l OCA], [https://pdbe.org/4k1l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k1l RCSB], [https://www.ebi.ac.uk/pdbsum/4k1l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k1l ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:[https://omim.org/entry/604931 604931]. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS).
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== Function ==
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[https://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true, potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ss-HSD1 revealed the unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g.
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==Function==
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1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ss-HSD1 inhibitors for the treatment of diabetes.,Bohme T, Engel CK, Farjot G, Gussregen S, Haack T, Tschank G, Ritter K Bioorg Med Chem Lett. 2013 Aug 15;23(16):4685-91. doi:, 10.1016/j.bmcl.2013.05.102. Epub 2013 Jun 11. PMID:23845218<ref>PMID:23845218</ref>
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[[http://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN]] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity).
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4k1l]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K1L OCA].
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</div>
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<div class="pdbe-citations 4k1l" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:023845218</ref><references group="xtra"/><references/>
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*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
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[[Category: 11-beta-hydroxysteroid dehydrogenase]]
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== References ==
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[[Category: Engel, C K.]]
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<references/>
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[[Category: Heyden, C Von der.]]
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__TOC__
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[[Category: Loenze, P.]]
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</StructureSection>
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[[Category: Schimanski-Breves, S.]]
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[[Category: Homo sapiens]]
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[[Category: 11-beta-hsd1]]
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[[Category: Large Structures]]
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[[Category: 11-beta-hydroxysteroid dehydrogenase 1]]
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[[Category: Engel CK]]
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[[Category: 11-dh]]
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[[Category: Loenze P]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Schimanski-Breves S]]
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[[Category: Short chain dehydrogenase]]
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[[Category: Von der Heyden C]]

Current revision

4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 beta-HSD1 inhibitors for the treatment of diabetes

PDB ID 4k1l

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