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| | ==Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with an orally bioavailable acidic inhibitor AZD4017.== | | ==Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with an orally bioavailable acidic inhibitor AZD4017.== |
| - | <StructureSection load='4hfr' size='340' side='right' caption='[[4hfr]], [[Resolution|resolution]] 2.73Å' scene=''> | + | <StructureSection load='4hfr' size='340' side='right'caption='[[4hfr]], [[Resolution|resolution]] 2.73Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4hfr]] is a 2 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=4HFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HFR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4hfr]] is a 2 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=4HFR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HFR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=14M:{(3S)-1-[5-(CYCLOHEXYLCARBAMOYL)-6-(PROPYLSULFANYL)PYRIDIN-2-YL]PIPERIDIN-3-YL}ACETIC+ACID'>14M</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=14M:{(3S)-1-[5-(CYCLOHEXYLCARBAMOYL)-6-(PROPYLSULFANYL)PYRIDIN-2-YL]PIPERIDIN-3-YL}ACETIC+ACID'>14M</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4hfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hfr OCA], [https://pdbe.org/4hfr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hfr RCSB], [https://www.ebi.ac.uk/pdbsum/4hfr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hfr ProSAT]</span></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=4hfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hfr OCA], [http://pdbe.org/4hfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hfr RCSB], [http://www.ebi.ac.uk/pdbsum/4hfr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hfr 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 4hfr" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4hfr" 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: Gerhardt, S]] | + | [[Category: Gerhardt S]] |
| - | [[Category: Hargreaves, D]] | + | [[Category: Hargreaves D]] |
| - | [[Category: Ogg, D J]] | + | [[Category: Ogg DJ]] |
| - | [[Category: Alpha beta]]
| + | |
| - | [[Category: Nadp]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Rossmann fold]]
| + | |
| 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
Inhibition of 11beta-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11beta-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.
Discovery of a potent, selective, and orally bioavailable acidic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acet ic acid (AZD4017).,Scott JS, Bowker SS, Deschoolmeester J, Gerhardt S, Hargreaves D, Kilgour E, Lloyd A, Mayers RM, McCoull W, Newcombe NJ, Ogg D, Packer MJ, Rees A, Revill J, Schofield P, Selmi N, Swales JG, Whittamore PR J Med Chem. 2012 Jun 28;55(12):5951-64. Epub 2012 Jun 19. PMID:22691057[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Scott JS, Bowker SS, Deschoolmeester J, Gerhardt S, Hargreaves D, Kilgour E, Lloyd A, Mayers RM, McCoull W, Newcombe NJ, Ogg D, Packer MJ, Rees A, Revill J, Schofield P, Selmi N, Swales JG, Whittamore PR. Discovery of a potent, selective, and orally bioavailable acidic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acet ic acid (AZD4017). J Med Chem. 2012 Jun 28;55(12):5951-64. Epub 2012 Jun 19. PMID:22691057 doi:http://dx.doi.org/10.1021/jm300592r
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