4c7k: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4c7k]] 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=4C7K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C7K FirstGlance]. <br> | <table><tr><td colspan='2'>[[4c7k]] 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=4C7K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C7K FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DZL:2-ETHYL-N-[(1S,3R)-5-OXIDANYL-2-ADAMANTYL]-4-[(2R)-OXOLAN-2-YL]-1,3-THIAZOLE-5-CARBOXAMIDE'>DZL</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]] 1.91Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DZL:2-ETHYL-N-[(1S,3R)-5-OXIDANYL-2-ADAMANTYL]-4-[(2R)-OXOLAN-2-YL]-1,3-THIAZOLE-5-CARBOXAMIDE'>DZL</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=4c7k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7k OCA], [https://pdbe.org/4c7k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c7k RCSB], [https://www.ebi.ac.uk/pdbsum/4c7k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c7k ProSAT]</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=4c7k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7k OCA], [https://pdbe.org/4c7k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c7k RCSB], [https://www.ebi.ac.uk/pdbsum/4c7k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c7k ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == 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 == | == 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 == | |||
11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11beta-HSD1 activity alleviates metabolic syndrome. | |||
Optimization of brain penetrant 11beta-hydroxysteroid dehydrogenase type I inhibitors and in vivo testing in diet-induced obese mice.,Goldberg FW, Dossetter AG, Scott JS, Robb GR, Boyd S, Groombridge SD, Kemmitt PD, Sjogren T, Gutierrez PM, deSchoolmeester J, Swales JG, Turnbull AV, Wild MJ J Med Chem. 2014 Feb 13;57(3):970-86. doi: 10.1021/jm4016729. Epub 2014 Jan 27. PMID:24422550<ref>PMID:24422550</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4c7k" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Latest revision as of 15:05, 20 December 2023
11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor
Structural highlights
DiseaseDHI1_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). FunctionDHI1_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 PubMed11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11beta-HSD1 activity alleviates metabolic syndrome. Optimization of brain penetrant 11beta-hydroxysteroid dehydrogenase type I inhibitors and in vivo testing in diet-induced obese mice.,Goldberg FW, Dossetter AG, Scott JS, Robb GR, Boyd S, Groombridge SD, Kemmitt PD, Sjogren T, Gutierrez PM, deSchoolmeester J, Swales JG, Turnbull AV, Wild MJ J Med Chem. 2014 Feb 13;57(3):970-86. doi: 10.1021/jm4016729. Epub 2014 Jan 27. PMID:24422550[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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