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| | <StructureSection load='6nj7' size='340' side='right'caption='[[6nj7]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='6nj7' size='340' side='right'caption='[[6nj7]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6nj7]] 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=6NJ7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NJ7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6nj7]] 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=6NJ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NJ7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7H6:(1S,4S,5S,9S)-9-hydroxy-8-methyl-4-(propan-2-yl)spiro[4.5]dec-7-ene-1-carboxylic+acid'>7H6</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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]] 2.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSD11B1, HSD11, HSD11L, SDR26C1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7H6:(1S,4S,5S,9S)-9-hydroxy-8-methyl-4-(propan-2-yl)spiro[4.5]dec-7-ene-1-carboxylic+acid'>7H6</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6nj7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nj7 OCA], [https://pdbe.org/6nj7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nj7 RCSB], [https://www.ebi.ac.uk/pdbsum/6nj7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nj7 ProSAT]</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=6nj7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nj7 OCA], [http://pdbe.org/6nj7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nj7 RCSB], [http://www.ebi.ac.uk/pdbsum/6nj7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nj7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == 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). | + | [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). |
| | == 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). | + | [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). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6nj7" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6nj7" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 11-beta-hydroxysteroid dehydrogenase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Miller, D J]] | + | [[Category: Miller DJ]] |
| - | [[Category: Rivas, F]] | + | [[Category: Rivas F]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Dehydrogenase]]
| + | |
| - | [[Category: Glucocorticoid regulation]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Disease
DHI1_HUMAN Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM: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
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).
Publication Abstract from PubMed
The natural product colletoic acid (CA) is a selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which primarily converts cortisone to the active glucocorticoid (GC) cortisol. Here, CA's mode of action and its potential as a chemical tool to study intracellular GC signaling in adipogenesis is disclosed. 11beta-HSD1 biochemical studies of CA indicated its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11beta-HSD1 bound to CA at 2.6 A resolution revealed the nature of those interactions, namely a close-fitting and favorable interactions between the constrained CA spirocycle, and the catalytic triad of 11beta-HSD1. Structure-Activity Relationship studies culminated in the development of a superior CA analogue with improved target engagement. Furthermore, we demonstrate that CA selectively inhibits preadipocyte differentiation through 11beta-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e. PPARgamma, PGC-1alpha), presumably by negatively modulating the glucocorticoid signaling pathway. The combined findings provide an in-depth evaluation of the mode of action of CA and its potential as a tool compound to study adipose tissue and its implications in metabolic syndrome.
Mechanistic insight on the mode of action of colletoic acid.,Ling T, Miller DJ, Lang W, Griffith E, Rodriguez-Cortes A, El Ayachi I, Palacios G, Min J, Miranda-Carboni GA, Lee RE, Rivas F J Med Chem. 2019 Jul 11. doi: 10.1021/acs.jmedchem.9b00187. PMID:31294974[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ling T, Miller DJ, Lang W, Griffith E, Rodriguez-Cortes A, El Ayachi I, Palacios G, Min J, Miranda-Carboni GA, Lee RE, Rivas F. Mechanistic insight on the mode of action of colletoic acid. J Med Chem. 2019 Jul 11. doi: 10.1021/acs.jmedchem.9b00187. PMID:31294974 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00187
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