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| | ==Crystal structure of h3alpha-hydroxysteroid dehydrogenase type 3 mutant Y24A in complex with NADP+ and epi-testosterone== | | ==Crystal structure of h3alpha-hydroxysteroid dehydrogenase type 3 mutant Y24A in complex with NADP+ and epi-testosterone== |
| - | <StructureSection load='2ipj' size='340' side='right' caption='[[2ipj]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='2ipj' size='340' side='right'caption='[[2ipj]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2ipj]] 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=2IPJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2IPJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2ipj]] 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=2IPJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IPJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FFA:(10ALPHA,13ALPHA,14BETA,17ALPHA)-17-HYDROXYANDROST-4-EN-3-ONE'>FFA</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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ipg|2ipg]], [[2ipf|2ipf]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FFA:(10ALPHA,13ALPHA,14BETA,17ALPHA)-17-HYDROXYANDROST-4-EN-3-ONE'>FFA</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1C2 ([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'>[https://proteopedia.org/fgij/fg.htm?mol=2ipj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ipj OCA], [https://pdbe.org/2ipj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ipj RCSB], [https://www.ebi.ac.uk/pdbsum/2ipj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ipj ProSAT]</span></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=2ipj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ipj OCA], [http://pdbe.org/2ipj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ipj RCSB], [http://www.ebi.ac.uk/pdbsum/2ipj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2ipj 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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </div> | | </div> |
| | <div class="pdbe-citations 2ipj" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 2ipj" 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: Breton, R]] | + | [[Category: Large Structures]] |
| - | [[Category: Cantin, L]] | + | [[Category: Breton R]] |
| - | [[Category: Faucher, F]] | + | [[Category: Cantin L]] |
| - | [[Category: Jesus-Tran, K Pereira de]] | + | [[Category: Faucher F]] |
| - | [[Category: Labrie, F]] | + | [[Category: Labrie F]] |
| - | [[Category: Luu-the, V]] | + | [[Category: Luu-the V]] |
| - | [[Category: 3a-hsd]] | + | [[Category: Pereira de Jesus-Tran K]] |
| - | [[Category: Akr]]
| + | |
| - | [[Category: Akr1c21]]
| + | |
| - | [[Category: Aldo-keto reductase]]
| + | |
| - | [[Category: Epi-testosterone]]
| + | |
| - | [[Category: Hsd]]
| + | |
| - | [[Category: Hydroxysteroid dehydrogenase]]
| + | |
| - | [[Category: Open conformation]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
2ipj is a 2 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 1.8Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The mouse 17alpha-hydroxysteroid dehydrogenase (m17alpha-HSD) is the unique known member of the aldo-keto reductase (AKR) superfamily able to catalyze efficiently and in a stereospecific manner the conversion of androstenedione (Delta4) into epi-testosterone (epi-T), the 17alpha-epimer of testosterone. Structural and mutagenic studies had already identified one of the residues delineating the steroid-binding cavity, A24, as the major molecular determinant for the stereospecificity of m17alpha-HSD. We report here a ternary complex crystal structure (m17alpha-HSD:NADP(+):epi-T) determined at 1.85 A resolution that confirms this and reveals a unique steroid-binding mode for an AKR enzyme. Indeed, in addition to the interactions found in all other AKRs (van der Waals contacts stabilizing the core of the steroid and the hydrogen bonds established at the catalytic site by the Y55 and H117 residues with the oxygen atom of the ketone group to be reduced), m17alpha-HSD establishes with the other extremity of the steroid nucleus an additional interaction involving K31. By combining direct mutagenesis and kinetic studies, we found that the elimination of this hydrogen bond did not affect the affinity of the enzyme for its steroid substrate but led to a slight but significant increase of its catalytic efficiency (k(cat)/K(m)), suggesting a role for K31 in the release of the steroidal product at the end of the reaction. This previously unobserved steroid-binding mode for an AKR is similar to that adopted by other steroid-binding proteins, the hydroxysteroid dehydrogenases of the short-chain dehydrogenases/reductases (SDR) family and the steroid hormone nuclear receptors. Mutagenesis and structural studies made on the human type 3 3alpha-HSD, a closely related enzyme that shares 73% amino acids identity with the m17alpha-HSD, also revealed that the residue at position 24 of these two enzymes directly affects the binding and/or the release of NADPH, in addition to its role in their 17alpha/17beta stereospecificity.
Mouse 17alpha-hydroxysteroid dehydrogenase (AKR1C21) binds steroids differently from other aldo-keto reductases: identification and characterization of amino acid residues critical for substrate binding.,Faucher F, Cantin L, Pereira de Jesus-Tran K, Lemieux M, Luu-The V, Labrie F, Breton R J Mol Biol. 2007 Jun 1;369(2):525-40. Epub 2007 Mar 27. PMID:17442338[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
- ↑ Faucher F, Cantin L, Pereira de Jesus-Tran K, Lemieux M, Luu-The V, Labrie F, Breton R. Mouse 17alpha-hydroxysteroid dehydrogenase (AKR1C21) binds steroids differently from other aldo-keto reductases: identification and characterization of amino acid residues critical for substrate binding. J Mol Biol. 2007 Jun 1;369(2):525-40. Epub 2007 Mar 27. PMID:17442338 doi:10.1016/j.jmb.2007.03.058
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