4k1l
From Proteopedia
(Difference between revisions)
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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== | |
| - | + | <StructureSection load='4k1l' size='340' side='right' caption='[[4k1l]], [[Resolution|resolution]] 1.96Å' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[4k1l]] is a 4 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=4K1L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K1L FirstGlance]. <br> | |
| - | ==Disease== | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSD11B1, HSD11, HSD11L ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/11-beta-hydroxysteroid_dehydrogenase 11-beta-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.146 1.1.1.146] </span></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=4k1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k1l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4k1l RCSB], [http://www.ebi.ac.uk/pdbsum/4k1l PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
[[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). | [[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). | ||
| - | + | == Function == | |
| - | ==Function== | + | |
[[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). | [[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). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| - | + | 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> | |
| - | [ | + | |
| - | == | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | + | </div> | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: 11-beta-hydroxysteroid dehydrogenase]] | [[Category: 11-beta-hydroxysteroid dehydrogenase]] | ||
| - | [[Category: Engel, C K | + | [[Category: Human]] |
| - | [[Category: Heyden, C Von der | + | [[Category: Engel, C K]] |
| - | [[Category: Loenze, P | + | [[Category: Heyden, C Von der]] |
| - | [[Category: Schimanski-Breves, S | + | [[Category: Loenze, P]] |
| + | [[Category: Schimanski-Breves, S]] | ||
[[Category: 11-beta-hsd1]] | [[Category: 11-beta-hsd1]] | ||
[[Category: 11-beta-hydroxysteroid dehydrogenase 1]] | [[Category: 11-beta-hydroxysteroid dehydrogenase 1]] | ||
Revision as of 13:33, 4 January 2015
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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