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[[Image:1afs.gif|left|200px]]


{{Structure
==RECOMBINANT RAT LIVER 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE (3-ALPHA-HSD) COMPLEXED WITH NADP AND TESTOSTERONE==
|PDB= 1afs |SIZE=350|CAPTION= <scene name='initialview01'>1afs</scene>, resolution 2.5&Aring;
<StructureSection load='1afs' size='340' side='right'caption='[[1afs]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene> and <scene name='pdbligand=TES:TESTOSTERONE'>TES</scene>
<table><tr><td colspan='2'>[[1afs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1AFS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1AFS FirstGlance]. <br>
|ACTIVITY= [http://en.wikipedia.org/wiki/3-alpha-hydroxysteroid_dehydrogenase_(B-specific) 3-alpha-hydroxysteroid dehydrogenase (B-specific)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.50 1.1.1.50]
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
|GENE=
<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=TES:TESTOSTERONE'>TES</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=1afs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1afs OCA], [https://pdbe.org/1afs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1afs RCSB], [https://www.ebi.ac.uk/pdbsum/1afs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1afs ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DIDH_RAT DIDH_RAT] Besides being a 3-alpha-hydroxysteroid dehydrogenase, the enzyme can accomplish diverse functions: as quinone reductase, as an aromatic alcohol dehydrogenase, as dihydrodiol dehydrogenase, and as 9-, 11-, and 15-hydroxyprostaglandin dehydrogenase.
== 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/af/1afs_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=1afs ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BACKGROUND: Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) modulate the activities of steroid hormones by reversibly reducing their C3 ketone groups. In steroid target tissues, 3 alpha-HSDs act on 5 alpha-dihydrotestosterone, a potent male sex hormone (androgen) implicated in benign prostate hyperplasia and prostate cancer. Rat liver 3 alpha-HSD belongs to the aldo-keto reductase (AKR) superfamily and provides a model for mammalian 3 alpha-, 17 beta- and 20 alpha-HSDs, which share &gt; 65% sequence identity. The determination of the structure of 3 alpha-HSD in complex with NADP+ and testosterone (a competitive inhibitor) will help to further our understanding of steroid recognition and hormone regulation by mammalian HSDs. RESULTS: We have determined the 2.5 A resolution crystal structure of recombinant rat liver 3 alpha-HSD complexed with NADP+ and testosterone. The structure provides the first picture of an HSD ternary complex in the AKR superfamily, and is the only structure to date of testosterone bound to a protein. It reveals that the C3 ketone in testosterone, corresponding to the reactive group in a substrate, is poised above the nicotinamide ring which is involved in hydride transfer. In addition, the C3 ketone forms hydrogen bonds with two active-site residues implicated in catalysis (Tyr55 and His117). CONCLUSIONS: The active-site arrangement observed in the 3 alpha-HSD ternary complex structure suggests that each positional-specific and stereospecific reaction catalyzed by an HSD requires a particular substrate orientation, the general features of which can be predicted. 3 alpha-HSDs are likely to bind substrates in a similar manner to the way in which testosterone is bound in the ternary complex, that is with the A ring of the steroid substrate in the active site and the beta face towards the nicotinamide ring to facilitate hydride transfer. In contrast, we predict that 17 beta-HSDs will bind substrates with the D ring of the steroid in the active site and with the alpha face towards the nicotinamide ring. The ability to bind substrates in only one or a few orientations could determine the positional-specificity and stereospecificity of each HSD. Residues lining the steroid-binding cavities are highly variable and may select these different orientations.


'''RECOMBINANT RAT LIVER 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE (3-ALPHA-HSD) COMPLEXED WITH NADP AND TESTOSTERONE'''
Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase.,Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis M Structure. 1997 Jun 15;5(6):799-812. PMID:9261071<ref>PMID:9261071</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1afs" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
BACKGROUND: Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) modulate the activities of steroid hormones by reversibly reducing their C3 ketone groups. In steroid target tissues, 3 alpha-HSDs act on 5 alpha-dihydrotestosterone, a potent male sex hormone (androgen) implicated in benign prostate hyperplasia and prostate cancer. Rat liver 3 alpha-HSD belongs to the aldo-keto reductase (AKR) superfamily and provides a model for mammalian 3 alpha-, 17 beta- and 20 alpha-HSDs, which share &gt; 65% sequence identity. The determination of the structure of 3 alpha-HSD in complex with NADP+ and testosterone (a competitive inhibitor) will help to further our understanding of steroid recognition and hormone regulation by mammalian HSDs. RESULTS: We have determined the 2.5 A resolution crystal structure of recombinant rat liver 3 alpha-HSD complexed with NADP+ and testosterone. The structure provides the first picture of an HSD ternary complex in the AKR superfamily, and is the only structure to date of testosterone bound to a protein. It reveals that the C3 ketone in testosterone, corresponding to the reactive group in a substrate, is poised above the nicotinamide ring which is involved in hydride transfer. In addition, the C3 ketone forms hydrogen bonds with two active-site residues implicated in catalysis (Tyr55 and His117). CONCLUSIONS: The active-site arrangement observed in the 3 alpha-HSD ternary complex structure suggests that each positional-specific and stereospecific reaction catalyzed by an HSD requires a particular substrate orientation, the general features of which can be predicted. 3 alpha-HSDs are likely to bind substrates in a similar manner to the way in which testosterone is bound in the ternary complex, that is with the A ring of the steroid substrate in the active site and the beta face towards the nicotinamide ring to facilitate hydride transfer. In contrast, we predict that 17 beta-HSDs will bind substrates with the D ring of the steroid in the active site and with the alpha face towards the nicotinamide ring. The ability to bind substrates in only one or a few orientations could determine the positional-specificity and stereospecificity of each HSD. Residues lining the steroid-binding cavities are highly variable and may select these different orientations.
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1AFS is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1AFS OCA].
__TOC__
 
</StructureSection>
==Reference==
[[Category: Large Structures]]
Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase., Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis M, Structure. 1997 Jun 15;5(6):799-812. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9261071 9261071]
[[Category: 3-alpha-hydroxysteroid dehydrogenase (B-specific)]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]
[[Category: Single protein]]
[[Category: Albert RH]]
[[Category: Albert, R H.]]
[[Category: Bennett MJ]]
[[Category: Bennett, M J.]]
[[Category: Jez JM]]
[[Category: Jez, J M.]]
[[Category: Lewis M]]
[[Category: Lewis, M.]]
[[Category: Ma H]]
[[Category: Ma, H.]]
[[Category: Penning TM]]
[[Category: Penning, T M.]]
[[Category: NAP]]
[[Category: TES]]
[[Category: nad]]
[[Category: oxidoreductase]]
 
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