2rbe: Difference between revisions

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New page: left|200px<br /><applet load="2rbe" size="350" color="white" frame="true" align="right" spinBox="true" caption="2rbe, resolution 1.900Å" /> '''The discovery of 2-...
 
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[[Image:2rbe.jpg|left|200px]]<br /><applet load="2rbe" size="350" color="white" frame="true" align="right" spinBox="true"
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'''The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors'''<br />


==Overview==
==The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors==
A series of 2-anilinothiazolones were prepared as inhibitors of, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent, compounds contained a 2-chloro or 2-fluoro group on the aniline ring with, an isopropyl substituent on the 5-position of the thiazolone ring, (compounds 2 and 3, respectively). The binding mode was determined through, the X-ray co-crystal structure of the enzyme with compound 3. This, compound was also approximately 70-fold selective over 11beta-HSD2 and was, orally bioavailable in rat pharmacokinetic studies. However, compound 3, was &gt;580-fold less active in the 11beta-HSD1 cell assay when tested in the, presence of 3% human serum albumin.
<StructureSection load='2rbe' size='340' side='right'caption='[[2rbe]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2rbe]] 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=2RBE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2RBE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=ZMG:(5R)-2-[(2-FLUOROPHENYL)AMINO]-5-(1-METHYLETHYL)-1,3-THIAZOL-4(5H)-ONE'>ZMG</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=2rbe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rbe OCA], [https://pdbe.org/2rbe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2rbe RCSB], [https://www.ebi.ac.uk/pdbsum/2rbe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2rbe 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/rb/2rbe_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=2rbe ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
2RBE 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=ZMG:'>ZMG</scene> and <scene name='pdbligand=NDP:'>NDP</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=2RBE OCA].
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
 
__TOC__
==Reference==
</StructureSection>
The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors., Yuan C, St Jean DJ Jr, Liu Q, Cai L, Li A, Han N, Moniz G, Askew B, Hungate RW, Johansson L, Tedenborg L, Pyring D, Williams M, Hale C, Chen M, Cupples R, Zhang J, Jordan S, Bartberger MD, Sun Y, Emery M, Wang M, Fotsch C, Bioorg Med Chem Lett. 2007 Nov 15;17(22):6056-61. Epub 2007 Sep 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17919905 17919905]
[[Category: 11-beta-hydroxysteroid dehydrogenase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Jordan, S.R.]]
[[Category: Jordan SR]]
[[Category: Li, V.]]
[[Category: Li V]]
[[Category: Zhang, J.]]
[[Category: Zhang J]]
[[Category: NDP]]
[[Category: ZMG]]
[[Category: 3-layer(aba) sandwich]]
[[Category: alpha beta]]
[[Category: endoplasmic reticulum]]
[[Category: glycoprotein]]
[[Category: lipid metabolism]]
[[Category: membrane]]
[[Category: microsome]]
[[Category: nad(p)-binding rossmann-like domain]]
[[Category: nadp]]
[[Category: oxidoreductase]]
[[Category: polymorphism]]
[[Category: rossmann fold]]
[[Category: signal-anchor]]
[[Category: steroid metabolism]]
[[Category: transmembrane]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 10:44:35 2008''

Latest revision as of 12:21, 21 February 2024

The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitorsThe discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors

Structural highlights

2rbe 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 1.9Å
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

2rbe, resolution 1.90Å

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