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| | ==Crystal structure of 11 beta-HSD1 in complex with SAR184841== | | ==Crystal structure of 11 beta-HSD1 in complex with SAR184841== |
| - | <StructureSection load='4hx5' size='340' side='right' caption='[[4hx5]], [[Resolution|resolution]] 2.19Å' scene=''> | + | <StructureSection load='4hx5' size='340' side='right'caption='[[4hx5]], [[Resolution|resolution]] 2.19Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4hx5]] 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=4HX5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HX5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4hx5]] 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=4HX5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HX5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19V:4-[5-(4-TERT-BUTYLPIPERAZIN-1-YL)PYRIDIN-2-YL]-N-[(1R,2S,3S,5S,7S)-5-CARBAMOYLTRICYCLO[3.3.1.1~3,7~]DEC-2-YL]-3,4-DIHYDROQUINOXALINE-1(2H)-CARBOXAMIDE'>19V</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=19V:4-[5-(4-TERT-BUTYLPIPERAZIN-1-YL)PYRIDIN-2-YL]-N-[(1R,2S,3S,5S,7S)-5-CARBAMOYLTRICYCLO[3.3.1.1~3,7~]DEC-2-YL]-3,4-DIHYDROQUINOXALINE-1(2H)-CARBOXAMIDE'>19V</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=4hx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hx5 OCA], [https://pdbe.org/4hx5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hx5 RCSB], [https://www.ebi.ac.uk/pdbsum/4hx5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hx5 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=4hx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hx5 OCA], [http://pdbe.org/4hx5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hx5 RCSB], [http://www.ebi.ac.uk/pdbsum/4hx5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hx5 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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| | ==See Also== | | ==See Also== |
| - | *[[Hydroxysteroid dehydrogenase|Hydroxysteroid dehydrogenase]] | + | *[[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: Engel, C K]] | + | [[Category: Engel CK]] |
| - | [[Category: Loenze, P]] | + | [[Category: Loenze P]] |
| - | [[Category: Schimanski-Breves, S]] | + | [[Category: Schimanski-Breves S]] |
| - | [[Category: Dehydrogenase]]
| + | |
| - | [[Category: Hydroxysteroid]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| 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
Starting from 11beta-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11beta-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.
Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D.,Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faihun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Farjot G, Noah L, Maniani K, Boutarfa A, Nicolai E, Guillot E, Pruniaux MP, Gussregen S, Engel C, Coutant AL, de Miguel B, Castro A Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018., Epub 2013 Feb 22. PMID:23478147[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faihun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Farjot G, Noah L, Maniani K, Boutarfa A, Nicolai E, Guillot E, Pruniaux MP, Gussregen S, Engel C, Coutant AL, de Miguel B, Castro A. Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D. Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018., Epub 2013 Feb 22. PMID:23478147 doi:10.1016/j.bmcl.2013.02.018
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