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6nj7
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==11-BETA DEHYDROGENASE ISOZYME 1 IN COMPLEX WITH COLLETOIC ACID== | |
| + | <StructureSection load='6nj7' size='340' side='right'caption='[[6nj7]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <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='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='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='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> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [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 == | ||
| + | [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;"> | ||
| + | == 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<ref>PMID:31294974</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6nj7" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Miller DJ]] | ||
| + | [[Category: Rivas F]] | ||
Current revision
11-BETA DEHYDROGENASE ISOZYME 1 IN COMPLEX WITH COLLETOIC ACID
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