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| | ==Crystal structure of human 3-alpha hydroxysteroid dehydrogenase type 3 in complex with NADP+, 5alpha-androstan-3,17-dione and (3beta, 5alpha)-3-hydroxyandrostan-17-one== | | ==Crystal structure of human 3-alpha hydroxysteroid dehydrogenase type 3 in complex with NADP+, 5alpha-androstan-3,17-dione and (3beta, 5alpha)-3-hydroxyandrostan-17-one== |
| - | <StructureSection load='4xo7' size='340' side='right' caption='[[4xo7]], [[Resolution|resolution]] 1.75Å' scene=''> | + | <StructureSection load='4xo7' size='340' side='right'caption='[[4xo7]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4xo7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XO7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XO7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4xo7]] is a 2 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=4XO7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XO7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ASD:4-ANDROSTENE-3-17-DIONE'>ASD</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ASD:4-ANDROSTENE-3-17-DIONE'>ASD</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4l1w|4l1w]], [[4nnf|4nnf]], [[4xo6|4xo6]]</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=4xo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xo7 OCA], [https://pdbe.org/4xo7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xo7 RCSB], [https://www.ebi.ac.uk/pdbsum/4xo7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xo7 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1C2, DDH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xo7 OCA], [http://pdbe.org/4xo7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xo7 RCSB], [http://www.ebi.ac.uk/pdbsum/4xo7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xo7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/AK1C2_HUMAN AK1C2_HUMAN]] Defects in AKR1C2 are a cause of 46,XY sex reversal type 8 (SRXY8) [MIM:[http://omim.org/entry/614279 614279]]. A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.<ref>PMID:21802064</ref> | + | [https://www.uniprot.org/uniprot/AK1C2_HUMAN AK1C2_HUMAN] Defects in AKR1C2 are a cause of 46,XY sex reversal type 8 (SRXY8) [MIM:[https://omim.org/entry/614279 614279]. A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.<ref>PMID:21802064</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AK1C2_HUMAN AK1C2_HUMAN]] Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability.<ref>PMID:8573067</ref> | + | [https://www.uniprot.org/uniprot/AK1C2_HUMAN AK1C2_HUMAN] Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability.<ref>PMID:8573067</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4xo7" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4xo7" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hu, X J]] | + | [[Category: Large Structures]] |
| - | [[Category: Lin, S X]] | + | [[Category: Hu X-J]] |
| - | [[Category: Zhang, B]]
| + | [[Category: Lin S-X]] |
| - | [[Category: Akr]]
| + | [[Category: Zhang B]] |
| - | [[Category: Akr1c2]]
| + | |
| - | [[Category: Aldo-keto reductase]]
| + | |
| - | [[Category: Alpha-beta barrel]] | + | |
| - | [[Category: Human 3-alpha hds3]] | + | |
| - | [[Category: Nadph]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Disease
AK1C2_HUMAN Defects in AKR1C2 are a cause of 46,XY sex reversal type 8 (SRXY8) [MIM:614279. A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.[1]
Function
AK1C2_HUMAN Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability.[2]
Publication Abstract from PubMed
Human 3alpha-HSD3 (3alpha-hydroxysteroid dehydrogenase type 3) plays an essential role in the inactivation of the most potent androgen 5alpha-DHT (5alpha-dihydrotestosterone). The present study attempts to obtain the important structure of 3alpha-HSD3 in complex with 5alpha-DHT and to investigate the role of 3alpha-HSD3 in breast cancer cells. We report the crystal structure of human 3alpha-HSD3.NADP(+).A-dione (5alpha-androstane-3,17-dione)/epi-ADT (epiandrosterone) complex, which was obtained by co-crystallization with 5alpha-DHT in the presence of NADP(+) Although 5alpha-DHT was introduced during the crystallization, oxidoreduction of 5alpha-DHT occurred. The locations of A-dione and epi-ADT were identified in the steroid-binding sites of two 3alpha-HSD3 molecules per crystal asymmetric unit. An overlay showed that A-dione and epi-ADT were oriented upside-down and flipped relative to each other, providing structural clues for 5alpha-DHT reverse binding in the enzyme with the generation of different products. Moreover, we report the crystal structure of the 3alpha-HSD3.NADP(+).4-dione (4-androstene-3,17-dione) complex. When a specific siRNA (100 nM) was used to suppress 3alpha-HSD3 expression without interfering with 3alpha-HSD4, which shares a highly homologous active site, the 5alpha-DHT concentration increased, whereas MCF7 cell growth was suppressed. The present study provides structural clues for 5alpha-DHT reverse binding within 3alpha-HSD3, and demonstrates for the first time that down-regulation of 3alpha-HSD3 decreases MCF7 breast cancer cell growth.
Human 3alpha-hydroxysteroid dehydrogenase type 3: structural clues of 5alpha-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth.,Zhang B, Hu XJ, Wang XQ, Theriault JF, Zhu DW, Shang P, Labrie F, Lin SX Biochem J. 2016 Apr 15;473(8):1037-46. doi: 10.1042/BCJ20160083. Epub 2016 Feb, 29. PMID:26929402[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fluck CE, Meyer-Boni M, Pandey AV, Kempna P, Miller WL, Schoenle EJ, Biason-Lauber A. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Am J Hum Genet. 2011 Aug 12;89(2):201-18. doi: 10.1016/j.ajhg.2011.06.009. Epub, 2011 Jul 28. PMID:21802064 doi:10.1016/j.ajhg.2011.06.009
- ↑ Hara A, Matsuura K, Tamada Y, Sato K, Miyabe Y, Deyashiki Y, Ishida N. Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells. Biochem J. 1996 Jan 15;313 ( Pt 2):373-6. PMID:8573067
- ↑ Zhang B, Hu XJ, Wang XQ, Theriault JF, Zhu DW, Shang P, Labrie F, Lin SX. Human 3alpha-hydroxysteroid dehydrogenase type 3: structural clues of 5alpha-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth. Biochem J. 2016 Apr 15;473(8):1037-46. doi: 10.1042/BCJ20160083. Epub 2016 Feb, 29. PMID:26929402 doi:http://dx.doi.org/10.1042/BCJ20160083
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