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1xu9

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[[Image:1xu9.jpg|left|200px]]<br /><applet load="1xu9" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1xu9, resolution 1.55&Aring;" />
 
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'''Crystal Structure of the Interface Closed Conformation of 11b-hydroxysteroid dehydrogenase isozyme 1'''<br />
 
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==Overview==
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==Crystal Structure of the Interface Closed Conformation of 11b-hydroxysteroid dehydrogenase isozyme 1==
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Human 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) is an, ER-localized membrane protein that catalyzes the interconversion of, cortisone and cortisol. In adipose tissue, excessive cortisol production, through 11beta-HSD1 activity has been implicated in the pathogenesis of, type II diabetes and obesity. We report here biophysical, kinetic, mutagenesis, and structural data on two ternary complexes of 11beta-HSD1., The combined results reveal flexible active site interactions relevant to, glucocorticoid recognition and demonstrate how four 11beta-HSD1 C termini, converge to form an as yet uncharacterized tetramerization motif. A, C-terminal Pro-Cys motif is localized at the center of the tetramer and, forms reversible enzyme disulfides that alter enzyme activity., Conformational flexibility at the tetramerization interface is coupled to, structural changes at the enzyme active site suggesting how the central, Pro-Cys motif may regulate enzyme activity. Together, the crystallographic, and biophysical data provide a structural framework for understanding, 11beta-HSD1 activities and will ultimately facilitate the development of, specific inhibitors.
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<StructureSection load='1xu9' size='340' side='right'caption='[[1xu9]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1xu9]] 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=1XU9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XU9 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]] 1.55&#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=CPS:3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE'>CPS</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=1xu9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xu9 OCA], [https://pdbe.org/1xu9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xu9 RCSB], [https://www.ebi.ac.uk/pdbsum/1xu9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xu9 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/xu/1xu9_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=1xu9 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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1XU9 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=NDP:'>NDP</scene>, <scene name='pdbligand=CPS:'>CPS</scene> and <scene name='pdbligand=MES:'>MES</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=1XU9 OCA].
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==Reference==
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Conformational flexibility in crystal structures of human 11beta-hydroxysteroid dehydrogenase type I provide insights into glucocorticoid interconversion and enzyme regulation., Hosfield DJ, Wu Y, Skene RJ, Hilgers M, Jennings A, Snell GP, Aertgeerts K, J Biol Chem. 2005 Feb 11;280(6):4639-48. Epub 2004 Oct 28. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15513927 15513927]
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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: Aertgeerts, K.]]
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[[Category: Aertgeerts K]]
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[[Category: Hilger, M.]]
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[[Category: Hilger M]]
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[[Category: Hosfield, D.J.]]
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[[Category: Hosfield DJ]]
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[[Category: Jennings, A.]]
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[[Category: Jennings A]]
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[[Category: Skene, R.J.]]
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[[Category: Skene RJ]]
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[[Category: Snell, G.P.]]
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[[Category: Snell GP]]
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[[Category: Wu, Y.]]
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[[Category: Wu Y]]
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[[Category: CPS]]
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[[Category: MES]]
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[[Category: NDP]]
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[[Category: 11beta]]
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[[Category: dehydrogenase]]
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[[Category: hydroxysteroid]]
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[[Category: sdr]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:10:26 2008''
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Current revision

Crystal Structure of the Interface Closed Conformation of 11b-hydroxysteroid dehydrogenase isozyme 1

PDB ID 1xu9

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