3uzx - Revision history

OCA at 14:12, 14 March 2024

OCA — Thu, 14 Mar 2024 14:12:31 GMT

←Older revision		Revision as of 14:12, 14 March 2024
Line 3:		Line 3:
	<StructureSection load='3uzx' size='340' side='right'caption='[[3uzx]], [[Resolution\|resolution]] 1.64Å' scene=''>		<StructureSection load='3uzx' size='340' side='right'caption='[[3uzx]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<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>	+	<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>
-	</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>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.637Å</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]], [[3uzy\|3uzy]], [[3uzz\|3uzz]]</div></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>
-	<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=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 ==
-	[[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 3uzx" style="background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__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

OCA — Wed, 20 Jul 2022 08:19:11 GMT

←Older revision		Revision as of 08:19, 20 July 2022
Line 1:		Line 1:

	==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone==		==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone==
-	<StructureSection load='3uzx' size='340' side='right' caption='[[3uzx]], [[Resolution\|resolution]] 1.64Å' scene=''>	+	<StructureSection load='3uzx' size='340' side='right'caption='[[3uzx]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3uzx]] 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=3UZX OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3UZX FirstGlance]. <br>	+	<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>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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>	+	</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>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3uzw\|3uzw]], [[3uzy\|3uzy]], [[3uzz\|3uzz]]</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]], [[3uzy\|3uzy]], [[3uzz\|3uzz]]</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=3uzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzx OCA], [~~http~~://pdbe.org/3uzx PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3uzx RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3uzx PDBsum], [~~http~~://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 ==
-	[[~~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 ==
Line 28:		Line 28:
	</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 10:32, 4 August 2016

OCA — Thu, 04 Aug 2016 10:32:57 GMT

←Older revision		Revision as of 10:32, 4 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone==		==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone==
	<StructureSection load='3uzx' size='340' side='right' caption='[[3uzx]], [[Resolution\|resolution]] 1.64Å' scene=''>		<StructureSection load='3uzx' size='340' side='right' caption='[[3uzx]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3uzx]] 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=3UZX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UZX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3uzx]] 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=3UZX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UZX FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3uzw\|3uzw]], [[3uzy\|3uzy]], [[3uzz\|3uzz]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3uzw\|3uzw]], [[3uzy\|3uzy]], [[3uzz\|3uzz]]</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=3uzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3uzx RCSB], [http://www.ebi.ac.uk/pdbsum/3uzx 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=3uzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzx OCA], [http://pdbe.org/3uzx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3uzx RCSB], [http://www.ebi.ac.uk/pdbsum/3uzx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3uzx ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	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 3uzx" 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 07:18, 21 December 2014

OCA — Sun, 21 Dec 2014 07:18:55 GMT

←Older revision		Revision as of 07:18, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_3uzx\| PDB=3uzx \| SCENE= }}~~	+	==Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone==
-	===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone===	+	<StructureSection load='3uzx' size='340' side='right' caption='[[3uzx]], [[Resolution\|resolution]] 1.64Å' scene=''>
-	~~{{ABSTRACT_PUBMED_22437839}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[3uzx]] 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=3UZX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UZX FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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>
-	[[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]], [[3uzy\|3uzy]], [[3uzz\|3uzz]]</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=3uzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uzx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3uzx RCSB], [http://www.ebi.ac.uk/pdbsum/3uzx 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>
-	~~[[3uzx]] 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=3UZX 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 16:37, 24 March 2013

OCA — Sun, 24 Mar 2013 16:37:21 GMT

←Older revision		Revision as of 16:37, 24 March 2013
Line 1:		Line 1:
-	[[Image:3uzx.png\|left\|200px]]
-
	{{STRUCTURE_3uzx\| PDB=3uzx \| SCENE= }}		{{STRUCTURE_3uzx\| PDB=3uzx \| SCENE= }}
-
	===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone===		===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone===
		+	{{ABSTRACT_PUBMED_22437839}}

-	~~{{ABSTRACT_PUBMED_22437839}}~~	+	==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.

	==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 04:59, 27 June 2012

OCA — Wed, 27 Jun 2012 04:59:19 GMT

←Older revision		Revision as of 04:59, 27 June 2012
Line 1:		Line 1:
-	[[Image:3uzx.~~jpg~~\|left\|200px]]	+	[[Image:3uzx.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3uzx", 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_3uzx\| PDB=3uzx \| SCENE= }}		{{STRUCTURE_3uzx\| PDB=3uzx \| SCENE= }}

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

		+	{{ABSTRACT_PUBMED_22437839}}

	==About this Structure==		==About this Structure==
	[[3uzx]] 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=3UZX OCA].		[[3uzx]] 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=3UZX 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

OCA — Wed, 21 Mar 2012 07:49:23 GMT

←Older revision		Revision as of 07:49, 21 March 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3uzx.jpg\|left\|200px]]

-	The ~~entry 3uzx~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3uzx", 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_3uzx\| PDB=3uzx \| SCENE= }}

-	~~Authors: Chen, M., Christianson, D.W., Penning, T.M.~~	+	===Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone===

-	~~Description: Crystal~~ structure ~~of 5beta~~-reductase ~~(AKR1D1) E120H~~ mutant ~~in complex with NADP+~~ and ~~epiandrosterone~~	+
		+	==About this Structure==
		+	[[3uzx]] 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=3UZX OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Chen, M.]]
		+	[[Category: Christianson, D W.]]
		+	[[Category: Penning, T M.]]
		+	[[Category: Aldo-keto reductase]]
		+	[[Category: Catalytic tetrad mutant]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Steroid and bile acid metabolism]]
		+	[[Category: Tim barrel]]

OCA at 05:44, 4 January 2012

OCA — Wed, 04 Jan 2012 05:44:35 GMT

←Older revision		Revision as of 05:44, 4 January 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3uzx is ON HOLD	+	The entry 3uzx 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 epiandrosterone		Description: Crystal structure of 5beta-reductase (AKR1D1) E120H mutant in complex with NADP+ and epiandrosterone

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

OCA — Wed, 14 Dec 2011 11:17:17 GMT

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

←Older revision

Revision as of 11:17, 14 December 2011

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

OCA — Wed, 14 Dec 2011 11:17:16 GMT

New page: '''Unreleased structure''' The entry 3uzx 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 3uzx 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 epiandrosterone