3uzz - Revision history

OCA at 14:12, 14 March 2024

2024-03-14T14:12:36Z

← Older revision		Revision as of 14:12, 14 March 2024
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	<StructureSection load='3uzz' size='340' side='right'caption='[[3uzz]], [[Resolution\|resolution]] 1.82Å' scene=''>		<StructureSection load='3uzz' size='340' side='right'caption='[[3uzz]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3uzz]] 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=3UZZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UZZ FirstGlance]. <br>		<table><tr><td colspan='2'>[[3uzz]] 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=3UZZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UZZ FirstGlance]. <br>
	</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TES:TESTOSTERONE'>TES</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]] 1.82Å</td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3uzw\|3uzw]], [[3uzx\|3uzx]], [[3uzy\|3uzy]]</div></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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TES:TESTOSTERONE'>TES</scene></td></tr>
	<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>
	<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>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3uzz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzz OCA], [https://pdbe.org/3uzz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uzz RCSB], [https://www.ebi.ac.uk/pdbsum/3uzz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzz 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=3uzz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzz OCA], [https://pdbe.org/3uzz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uzz RCSB], [https://www.ebi.ac.uk/pdbsum/3uzz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[[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>		[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 ==
	[[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.		[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.
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	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.

	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>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 3uzz" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Chen, M]]		[[Category: Chen M]]
	[[Category: Christianson~~, D W~~]]		[[Category: Christianson DW]]
	[[Category: Penning~~, T M]]~~		[[Category: Penning TM]]
	~~[[Category: Aldo-keto reductase]]~~
	~~[[Category: Catalytic tetrad mutant]]~~
	~~[[Category: Oxidoreductase]]~~
	~~[[Category: Steroid and bile acid metabolism]]~~
	~~[[Category: Tim barrel~~]]

OCA at 08:19, 20 July 2022

2022-07-20T08:19:19Z

← Older revision		Revision as of 08:19, 20 July 2022
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	==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione==		==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione==
	<StructureSection load='3uzz' size='340' side='right' caption='[[3uzz]], [[Resolution\|resolution]] 1.82Å' scene=''>		<StructureSection load='3uzz' size='340' side='right'caption='[[3uzz]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3uzz]] 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=3UZZ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3UZZ FirstGlance]. <br>		<table><tr><td colspan='2'>[[3uzz]] 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=3UZZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UZZ 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TES:TESTOSTERONE'>TES</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TES:TESTOSTERONE'>TES</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3uzw\|3uzw]], [[3uzx\|3uzx]], [[3uzy\|3uzy]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3uzw\|3uzw]], [[3uzx\|3uzx]], [[3uzy\|3uzy]]</div></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKR1D1, SRD5B1 ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<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>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/Delta(4)-3-oxosteroid_5-beta-reductase Delta(4)-3-oxosteroid 5-beta-reductase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.3 1.3.1.3] </span></td></tr>		<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>
	<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=3uzz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzz OCA], [~~http~~://pdbe.org/3uzz PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3uzz RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3uzz PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzz 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=3uzz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzz OCA], [https://pdbe.org/3uzz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uzz RCSB], [https://www.ebi.ac.uk/pdbsum/3uzz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[[~~http~~://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[~~http~~://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>		[[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 ==
	[[~~http~~://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.		[[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.
	<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 3uzz" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3uzz" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Aldo-keto reductase 3D structures\|Aldo-keto reductase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
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	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
			[[Category: Large Structures]]
	[[Category: Chen, M]]		[[Category: Chen, M]]
	[[Category: Christianson, D W]]		[[Category: Christianson, D W]]

OCA at 08:16, 4 August 2016

2016-08-04T08:16:02Z

← Older revision		Revision as of 08:16, 4 August 2016
Line 1:		Line 1:

	==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione==		==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione==
	<StructureSection load='3uzz' size='340' side='right' caption='[[3uzz]], [[Resolution\|resolution]] 1.82Å' scene=''>		<StructureSection load='3uzz' size='340' side='right' caption='[[3uzz]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3uzz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UZZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UZZ FirstGlance]. <br>		<table><tr><td colspan='2'>[[3uzz]] 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=3UZZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UZZ 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TES:TESTOSTERONE'>TES</scene></td></tr>		</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TES:TESTOSTERONE'>TES</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3uzw\|3uzw]], [[3uzx\|3uzx]], [[3uzy\|3uzy]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3uzw\|3uzw]], [[3uzx\|3uzx]], [[3uzy\|3uzy]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKR1D1, SRD5B1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKR1D1, SRD5B1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Delta(4)-3-oxosteroid_5-beta-reductase Delta(4)-3-oxosteroid 5-beta-reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.3 1.3.1.3] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Delta(4)-3-oxosteroid_5-beta-reductase Delta(4)-3-oxosteroid 5-beta-reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.3 1.3.1.3] </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=3uzz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3uzz RCSB], [http://www.ebi.ac.uk/pdbsum/3uzz PDBsum]</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=3uzz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzz OCA], [http://pdbe.org/3uzz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3uzz RCSB], [http://www.ebi.ac.uk/pdbsum/3uzz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
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	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 3uzz" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Homo sapiens~~]]		[[Category: Human]]
	[[Category: Chen, M]]		[[Category: Chen, M]]
	[[Category: Christianson, D W]]		[[Category: Christianson, D W]]

OCA at 07:29, 21 December 2014

2014-12-21T07:29:57Z

← Older revision		Revision as of 07:29, 21 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_3uzz\| PDB=3uzz \| SCENE= }}~~		==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione==
	===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione===		<StructureSection load='3uzz' size='340' side='right' caption='[[3uzz]], [[Resolution\|resolution]] 1.82Å' scene=''>
	~~{{ABSTRACT_PUBMED_22437839}}~~		== Structural highlights ==
			<table><tr><td colspan='2'>[[3uzz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UZZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UZZ FirstGlance]. <br>
	==Disease==		</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TES:TESTOSTERONE'>TES</scene></td></tr>
	[[http://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[http://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>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3uzw\|3uzw]], [[3uzx\|3uzx]], [[3uzy\|3uzy]]</td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKR1D1, SRD5B1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
	==Function==		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Delta(4)-3-oxosteroid_5-beta-reductase Delta(4)-3-oxosteroid 5-beta-reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.3 1.3.1.3] </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=3uzz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3uzz RCSB], [http://www.ebi.ac.uk/pdbsum/3uzz PDBsum]</span></td></tr>
			</table>
			== Disease ==
			[[http://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[http://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 ==
	[[http://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.		[[http://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.
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			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.

	~~==About this Structure==~~		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>
	~~[[3uzz]] is a 2 chain structure with sequence from [http~~:~~//en.wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http~~:~~//oca~~.~~weizmann~~.~~ac.il/oca-bin~~/~~ocashort?id=3UZZ OCA].~~

	==~~Reference~~==		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~<ref group="xtra">PMID:022437839</ref>~~<references ~~group="xtra"~~/><~~references~~/>		</div>
			== References ==
			<references/>
			__TOC__
			</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Chen, M.]]		[[Category: Chen, M]]
	[[Category: Christianson, D W.]]		[[Category: Christianson, D W]]
	[[Category: Penning, T M.]]		[[Category: Penning, T M]]
	[[Category: Aldo-keto reductase]]		[[Category: Aldo-keto reductase]]
	[[Category: Catalytic tetrad mutant]]		[[Category: Catalytic tetrad mutant]]

OCA at 10:23, 24 March 2013

2013-03-24T10:23:07Z

← Older revision		Revision as of 10:23, 24 March 2013
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	~~[[Image:3uzz.png\|left\|200px]]~~

	{{STRUCTURE_3uzz\| PDB=3uzz \| SCENE= }}		{{STRUCTURE_3uzz\| PDB=3uzz \| SCENE= }}
			===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione===
			{{ABSTRACT_PUBMED_22437839}}

	===~~Crystal structure~~ of ~~5beta~~-reductase ~~(AKR1D1) E120H mutant~~ in ~~complex with NADP+~~ and ~~delta4-androstenedione===~~		==Disease==
			[[http://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[http://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>

	~~{{ABSTRACT_PUBMED_22437839}}~~		==Function==
			[[http://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.

	==About this Structure==		==About this Structure==
Line 11:		Line 13:

	==Reference==		==Reference==
	<ref group="xtra">PMID:022437839</ref><references group="xtra"/>		<ref group="xtra">PMID:022437839</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Chen, M.]]		[[Category: Chen, M.]]

OCA at 04:42, 27 June 2012

2012-06-27T04:42:55Z

← Older revision		Revision as of 04:42, 27 June 2012
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	[[Image:3uzz.~~jpg~~\|left\|200px]]		[[Image:3uzz.png\|left\|200px]]

	~~<!--~~
	~~The line below this paragraph, containing "STRUCTURE_3uzz", creates the "Structure Box" on the page.~~
	~~You may change the PDB parameter (which sets the PDB file loaded into the applet)~~
	~~or the SCENE parameter (which sets the initial scene displayed when the page is loaded),~~
	~~or leave the SCENE parameter empty for the default display.~~
	~~-->~~
	{{STRUCTURE_3uzz\| PDB=3uzz \| SCENE= }}		{{STRUCTURE_3uzz\| PDB=3uzz \| SCENE= }}

	===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione===		===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione===

			{{ABSTRACT_PUBMED_22437839}}

	==About this Structure==		==About this Structure==
	[[3uzz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UZZ OCA].		[[3uzz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UZZ OCA].

			==Reference==
			<ref group="xtra">PMID:022437839</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Chen, M.]]		[[Category: Chen, M.]]

OCA at 07:49, 21 March 2012

2012-03-21T07:49:31Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+[[Image:3uzz.jpg|left|200px]]
-The entry 3uzz is ON HOLD  until Paper Publication
+<!--
-Authors: Chen, M., Christianson, D.W., Penning, T.M.
+===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione===
-Description: Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione

OCA at 05:44, 4 January 2012

2012-01-04T05:44:38Z

← Older revision		Revision as of 05:44, 4 January 2012
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 3uzz is ON HOLD		The entry 3uzz is ON HOLD until Paper Publication

	Authors: Chen, M., Christianson, D.W., Penning, T.M.		Authors: Chen, M., Christianson, D.W., Penning, T.M.

	Description: Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione		Description: Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione

OCA: Protected "3uzz" [edit=sysop:move=sysop]

2011-12-14T11:17:21Z

Protected "3uzz" [edit=sysop:move=sysop]

← Older revision	Revision as of 11:17, 14 December 2011
(No difference)

OCA: New page: '''Unreleased structure''' The entry 3uzz is ON HOLD Authors: Chen, M., Christianson, D.W., Penning, T.M. Description: Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in com...

2011-12-14T11:17:20Z

New page: '''Unreleased structure''' The entry 3uzz is ON HOLD Authors: Chen, M., Christianson, D.W., Penning, T.M. Description: Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in com...

New page

'''Unreleased structure'''

The entry 3uzz is ON HOLD

Authors: Chen, M., Christianson, D.W., Penning, T.M.

Description: Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and delta4-androstenedione