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[[Image:3bzu.jpg|left|200px]]


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==Crystal structure of human 11-beta-hydroxysteroid dehydrogenase(HSD1) in complex with NADP and thiazolone inhibitor==
The line below this paragraph, containing "STRUCTURE_3bzu", creates the "Structure Box" on the page.
<StructureSection load='3bzu' size='340' side='right'caption='[[3bzu]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[3bzu]] 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=3BZU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BZU FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25&#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=A21:(5S)-2-{[(1S)-1-(2-FLUOROPHENYL)ETHYL]AMINO}-5-METHYL-5-(TRIFLUOROMETHYL)-1,3-THIAZOL-4(5H)-ONE'>A21</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
{{STRUCTURE_3bzu| PDB=3bzu |  SCENE= }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bzu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bzu OCA], [https://pdbe.org/3bzu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bzu RCSB], [https://www.ebi.ac.uk/pdbsum/3bzu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bzu ProSAT]</span></td></tr>
</table>
== 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 ==
[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).
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bz/3bzu_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=3bzu ConSurf].
<div style="clear:both"></div>


'''Crystal structure of human 11-beta-hydroxysteroid dehydrogenase(HSD1) in complex with NADP and thiazolone inhibitor'''
==See Also==
 
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
 
__TOC__
==Overview==
</StructureSection>
11Beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid action and inhibition of this enzyme is a viable therapeutic strategy for the treatment of type 2 diabetes and the metabolic syndrome. Here, we report a potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor with a binding mode elucidated from the co-crystal structure with the human 11beta-hydroxysteroid dehydrogenase type 1. The inhibitor is bound to the steroid-binding pocket making contacts with the catalytic center and the solvent channel. The inhibitor binding is facilitated by two direct hydrogen bond interactions involving Tyrosine183 of the catalytic motif Tyr-X-X-X-Lys and Alanine172. In addition, the inhibitor makes many hydrophobic interactions with both the enzyme and the co-factor nicotinamide adenine dinucleotide phosphate (reduced). In lean C57BL/6 mice, the compound inhibited both the in vivo and ex vivo 11beta-hydroxysteroid dehydrogenase type 1 activities in a dose-dependent manner. The inhibitory effects correlate with the plasma compound concentrations, suggesting that there is a clear pharmacokinetic and pharmacodynamic relationship. Moreover, at the same doses used in the pharmacokinetic/pharmacodynamic studies, the inhibitor did not cause the activation of the hypothalamic-pituitary-adrenal axis in an acute mouse model, suggesting that this compound exhibits biological effects with minimal risk of activating the hypothalamic-pituitary-adrenal axis.
 
==About this Structure==
3BZU is a [[Single protein]] structure of 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=3BZU OCA].
 
==Reference==
Structural characterization and pharmacodynamic effects of an orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor., Hale C, Veniant M, Wang Z, Chen M, McCormick J, Cupples R, Hickman D, Min X, Sudom A, Xu H, Matsumoto G, Fotsch C, St Jean DJ Jr, Wang M, Chem Biol Drug Des. 2008 Jan;71(1):36-44. Epub 2007 Dec 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18069989 18069989]
[[Category: 11-beta-hydroxysteroid dehydrogenase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Min, X.]]
[[Category: Min X]]
[[Category: Sudom, A.]]
[[Category: Sudom A]]
[[Category: Walker, N P.]]
[[Category: Walker NP]]
[[Category: Wang, Z.]]
[[Category: Wang Z]]
[[Category: Xu, H.]]
[[Category: Xu H]]
[[Category: 11beta hydroxysteroid dehydrogenase]]
[[Category: Endoplasmic reticulum]]
[[Category: Glycoprotein]]
[[Category: Lipid metabolism]]
[[Category: Membrane]]
[[Category: Microsome]]
[[Category: Nadp]]
[[Category: Oxidoreductase]]
[[Category: Polymorphism]]
[[Category: Signal-anchor]]
[[Category: Steroid metabolism]]
[[Category: Transmembrane]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 10:48:00 2008''

Latest revision as of 12:32, 21 February 2024

Crystal structure of human 11-beta-hydroxysteroid dehydrogenase(HSD1) in complex with NADP and thiazolone inhibitorCrystal structure of human 11-beta-hydroxysteroid dehydrogenase(HSD1) in complex with NADP and thiazolone inhibitor

Structural highlights

3bzu is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.25Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

3bzu, resolution 2.25Å

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