4hfr

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{{STRUCTURE_4hfr| PDB=4hfr | SCENE= }}
 
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===Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with an orally bioavailable acidic inhibitor AZD4017.===
 
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{{ABSTRACT_PUBMED_22691057}}
 
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==Disease==
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==Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with an orally bioavailable acidic inhibitor AZD4017.==
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[[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).
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<StructureSection load='4hfr' size='340' side='right'caption='[[4hfr]], [[Resolution|resolution]] 2.73&Aring;' scene=''>
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== Structural highlights ==
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<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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.73&#8491;</td></tr>
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<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>
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<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>
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</table>
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== Disease ==
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[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).
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== Function ==
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[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).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Function==
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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<ref>PMID:22691057</ref>
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[[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).
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4hfr]] is a 2 chain structure with sequence from [http://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].
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</div>
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[[Category: 11-beta-hydroxysteroid dehydrogenase]]
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<div class="pdbe-citations 4hfr" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Gerhardt, S.]]
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[[Category: Large Structures]]
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[[Category: Hargreaves, D]]
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[[Category: Gerhardt S]]
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[[Category: Ogg, D J.]]
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[[Category: Hargreaves D]]
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[[Category: Alpha beta]]
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[[Category: Ogg DJ]]
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[[Category: Nadp]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Rossman fold]]
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Current revision

Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with an orally bioavailable acidic inhibitor AZD4017.

PDB ID 4hfr

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