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| | ==CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-[2-(4-fluorophenyl)-2-adamantyl]-1-(3-methoxyazetidin-1-yl)ethanone== | | ==CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-[2-(4-fluorophenyl)-2-adamantyl]-1-(3-methoxyazetidin-1-yl)ethanone== |
| - | <StructureSection load='5pgu' size='340' side='right' caption='[[5pgu]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='5pgu' size='340' side='right'caption='[[5pgu]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5pgu]] 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=5PGU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5PGU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5pgu]] 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=5PGU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5PGU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8K4:2-[2-(4-fluorophenyl)-2-adamantyl]-1-(3-methoxyazetidin-1-yl)ethanone'>8K4</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]] 2.35Å</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=8K4:2-[2-(4-fluorophenyl)-2-adamantyl]-1-(3-methoxyazetidin-1-yl)ethanone'>8K4</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=5pgu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pgu OCA], [https://pdbe.org/5pgu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5pgu RCSB], [https://www.ebi.ac.uk/pdbsum/5pgu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5pgu 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=5pgu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pgu OCA], [http://pdbe.org/5pgu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5pgu RCSB], [http://www.ebi.ac.uk/pdbsum/5pgu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5pgu 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;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11beta-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.
| + | |
| | | | |
| - | Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.,Ye XY, Chen SY, Wu S, Yoon DS, Wang H, Hong Z, O'Connor SP, Li J, Li JJ, Kennedy LJ, Walker SJ, Nayeem A, Sheriff S, Camac DM, Ramamurthy V, Morin PE, Zebo R, Taylor JR, Morgan NN, Ponticiello RP, Harrity T, Apedo A, Golla R, Seethala R, Wang M, Harper TW, Sleczka BG, He B, Kirby M, Leahy DK, Li J, Hanson RL, Guo Z, Li YX, DiMarco JD, Scaringe R, Maxwell B, Moulin F, Barrish JC, Gordon DA, Robl JA J Med Chem. 2017 Jun 22;60(12):4932-4948. doi: 10.1021/acs.jmedchem.7b00211. Epub, 2017 Jun 5. PMID:28537398<ref>PMID:28537398</ref>
| + | ==See Also== |
| - | | + | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5pgu" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 11-beta-hydroxysteroid dehydrogenase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Sheriff, S]] | + | [[Category: Sheriff S]] |
| - | [[Category: 11b-hsd1]]
| + | |
| - | [[Category: Dehydrogenase]]
| + | |
| - | [[Category: Hydroxysteroid]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibi complex]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Sdr]]
| + | |
