2irw

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[[Image:2irw.gif|left|200px]]<br /><applet load="2irw" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2irw, resolution 3.100&Aring;" />
 
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'''Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) with NADP and Adamantane Ether Inhibitor'''<br />
 
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==Overview==
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==Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) with NADP and Adamantane Ether Inhibitor==
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A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
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<StructureSection load='2irw' size='340' side='right'caption='[[2irw]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2irw]] is a 8 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=2IRW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IRW 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]] 3.1&#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=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=NN4:(1S,3R,4S,5S,7S)-4-{[2-(4-METHOXYPHENOXY)-2-METHYLPROPANOYL]AMINO}ADAMANTANE-1-CARBOXAMIDE'>NN4</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=2irw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2irw OCA], [https://pdbe.org/2irw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2irw RCSB], [https://www.ebi.ac.uk/pdbsum/2irw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2irw 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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ir/2irw_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2irw ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Cortisone reductase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600713 600713]]
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*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
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__TOC__
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==About this Structure==
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</StructureSection>
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2IRW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=NN4:'>NN4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IRW OCA].
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==Reference==
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Discovery of adamantane ethers as inhibitors of 11beta-HSD-1: Synthesis and biological evaluation., Patel JR, Shuai Q, Dinges J, Winn M, Pliushchev M, Fung S, Monzon K, Chiou W, Wang J, Pan L, Wagaw S, Engstrom K, Kerdesky FA, Longenecker K, Judge R, Qin W, Imade HM, Stolarik D, Beno DW, Brune M, Chovan LE, Sham HL, Jacobson P, Link JT, Bioorg Med Chem Lett. 2007 Feb 1;17(3):750-5. Epub 2006 Oct 28. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17110106 17110106]
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[[Category: 11-beta-hydroxysteroid dehydrogenase]]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Longenecker, K L.]]
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[[Category: Longenecker KL]]
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[[Category: Patel, J R]]
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[[Category: Patel JR]]
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[[Category: Qin, W.]]
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[[Category: Qin W]]
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[[Category: Russell, J.]]
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[[Category: Russell J]]
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[[Category: NAP]]
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[[Category: NN4]]
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[[Category: hsd1]]
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[[Category: inhibitor]]
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[[Category: nadp]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:55:21 2008''
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Current revision

Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) with NADP and Adamantane Ether Inhibitor

PDB ID 2irw

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