3uzx

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Current revision (14:12, 14 March 2024) (edit) (undo)
 
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<StructureSection load='3uzx' size='340' side='right'caption='[[3uzx]], [[Resolution|resolution]] 1.64&Aring;' scene=''>
<StructureSection load='3uzx' size='340' side='right'caption='[[3uzx]], [[Resolution|resolution]] 1.64&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3uzx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UZX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UZX FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3uzx]] 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=3UZX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UZX FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AOM:5-ALPHA-ANDROSTANE-3-BETA,17BETA-DIOL'>AOM</scene>, <scene name='pdbligand=AOX:(3BETA,5ALPHA)-3-HYDROXYANDROSTAN-17-ONE'>AOX</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.637&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3uzw|3uzw]], [[3uzy|3uzy]], [[3uzz|3uzz]]</div></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=AOM:5-ALPHA-ANDROSTANE-3-BETA,17BETA-DIOL'>AOM</scene>, <scene name='pdbligand=AOX:(3BETA,5ALPHA)-3-HYDROXYANDROSTAN-17-ONE'>AOX</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1D1, SRD5B1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Delta(4)-3-oxosteroid_5-beta-reductase Delta(4)-3-oxosteroid 5-beta-reductase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.3 1.3.1.3] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3uzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzx OCA], [https://pdbe.org/3uzx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uzx RCSB], [https://www.ebi.ac.uk/pdbsum/3uzx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzx ProSAT]</span></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=3uzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzx OCA], [https://pdbe.org/3uzx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uzx RCSB], [https://www.ebi.ac.uk/pdbsum/3uzx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzx ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[https://omim.org/entry/235555 235555]]; also known as cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine.<ref>PMID:12970144</ref> <ref>PMID:15030995</ref>
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[https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[https://omim.org/entry/235555 235555]; also known as cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine.<ref>PMID:12970144</ref> <ref>PMID:15030995</ref>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates.
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[https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN] Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5beta-reduction of Delta(4)-3-ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His(120) (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5beta-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5alpha-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3beta-HSD as opposed to a 3alpha-HSD. The catalytic efficiency achieved for 3beta-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5beta-dihydrotestosterone, and Delta(4)-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the Delta(4)-double bond and confers 3beta-HSD activity on the 5beta-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its alpha-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.
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Conversion of human steroid 5beta-reductase (AKR1D1) into 3beta-hydroxysteroid dehydrogenase by single point mutation E120H: example of perfect enzyme engineering.,Chen M, Drury JE, Christianson DW, Penning TM J Biol Chem. 2012 May 11;287(20):16609-22. Epub 2012 Mar 20. PMID:22437839<ref>PMID:22437839</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3uzx" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Chen, M]]
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[[Category: Chen M]]
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[[Category: Christianson, D W]]
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[[Category: Christianson DW]]
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[[Category: Penning, T M]]
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[[Category: Penning TM]]
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[[Category: Aldo-keto reductase]]
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[[Category: Catalytic tetrad mutant]]
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[[Category: Oxidoreductase]]
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[[Category: Steroid and bile acid metabolism]]
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[[Category: Tim barrel]]
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Current revision

Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone

PDB ID 3uzx

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OCA

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