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==Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase 1 (11b-HSD1) in Complex with 4,4-Disubstituted Cyclohexylbenzamide Inhibitor== | ==Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase 1 (11b-HSD1) in Complex with 4,4-Disubstituted Cyclohexylbenzamide Inhibitor== | ||
<StructureSection load='3pdj' size='340' side='right' caption='[[3pdj]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='3pdj' size='340' side='right' caption='[[3pdj]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3pdj]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3pdj]] 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=3PDJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3PDJ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PJ:N-[TRANS-4-(3-AMINO-3-OXOPROPYL)-4-PHENYLCYCLOHEXYL]-N-CYCLOPROPYL-4-[(1S)-2,2,2-TRIFLUORO-1-HYDROXY-1-METHYLETHYL]BENZAMIDE'>3PJ</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"><scene name='pdbligand=3PJ:N-[TRANS-4-(3-AMINO-3-OXOPROPYL)-4-PHENYLCYCLOHEXYL]-N-CYCLOPROPYL-4-[(1S)-2,2,2-TRIFLUORO-1-HYDROXY-1-METHYLETHYL]BENZAMIDE'>3PJ</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3d4n|3d4n]], [[3d3e|3d3e]], [[3czr|3czr]], [[3bzu|3bzu]], [[3frj|3frj]], [[3fco|3fco]], [[3d5q|3d5q]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3d4n|3d4n]], [[3d3e|3d3e]], [[3czr|3czr]], [[3bzu|3bzu]], [[3frj|3frj]], [[3fco|3fco]], [[3d5q|3d5q]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSD11, HSD11B1, HSD11L ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSD11, HSD11B1, HSD11L ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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=3pdj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pdj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3pdj RCSB], [http://www.ebi.ac.uk/pdbsum/3pdj PDBsum]</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=3pdj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pdj OCA], [http://pdbe.org/3pdj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3pdj RCSB], [http://www.ebi.ac.uk/pdbsum/3pdj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3pdj ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
| Line 21: | Line 22: | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3pdj" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
| Line 29: | Line 31: | ||
</StructureSection> | </StructureSection> | ||
[[Category: 11-beta-hydroxysteroid dehydrogenase]] | [[Category: 11-beta-hydroxysteroid dehydrogenase]] | ||
[[Category: | [[Category: Human]] | ||
[[Category: Sudom, A]] | [[Category: Sudom, A]] | ||
[[Category: Walker, N P]] | [[Category: Walker, N P]] | ||
Revision as of 18:40, 4 August 2016
Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase 1 (11b-HSD1) in Complex with 4,4-Disubstituted Cyclohexylbenzamide InhibitorCrystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase 1 (11b-HSD1) in Complex with 4,4-Disubstituted Cyclohexylbenzamide Inhibitor
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 PubMedThe synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models. Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11beta-HSD1 inhibitors.,Sun D, Wang Z, Caille S, DeGraffenreid M, Gonzalez-Lopez de Turiso F, Hungate R, Jaen JC, Jiang B, Julian LD, Kelly R, McMinn DL, Kaizerman J, Rew Y, Sudom A, Tu H, Ursu S, Walker N, Willcockson M, Yan X, Ye Q, Powers JP Bioorg Med Chem Lett. 2011 Jan 1;21(1):405-10. Epub 2010 Oct 31. PMID:21093258[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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