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3g1r

From Proteopedia

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Crystal structure of human liver 5beta-reductase (AKR1D1) in complex with NADP and Finasteride. Resolution 1.70 A

Structural highlights

3g1r 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 1.701Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AK1D1_HUMAN Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM: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.^[1] ^[2]

Function

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.

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 Delta(4)-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens. The first step in functionalization of the A-ring is mediated in humans by steroid 5alpha- or 5beta-reductase. Finasteride is a mechanism-based inactivator of 5alpha-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia. It is also used for androgen deprivation in hormone-dependent prostate carcinoma, and it has been examined as a chemopreventive agent in prostate cancer. The effect of finasteride on steroid 5beta-reductase (AKR1D1) has not been previously reported. We show that finasteride competitively inhibits AKR1D1 with low micromolar affinity but does not act as a mechanism-based inactivator. The structure of the AKR1D1.NADP(+)*finasteride complex determined at 1.7 A resolution shows that it is not possible for NADPH to reduce the Delta(1-2)-ene of finasteride because the cofactor and steroid are not proximal to each other. The C3-ketone of finasteride accepts hydrogen bonds from the catalytic residues Tyr-58 and Glu-120 in the active site of AKR1D1, providing an explanation for the competitive inhibition observed. This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.

Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex.,Drury JE, Di Costanzo L, Penning TM, Christianson DW J Biol Chem. 2009 Jul 24;284(30):19786-90. Epub 2009 Jun 10. PMID:19515843^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lemonde HA, Custard EJ, Bouquet J, Duran M, Overmars H, Scambler PJ, Clayton PT. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003 Oct;52(10):1494-9. PMID:12970144
↑ Gonzales E, Cresteil D, Baussan C, Dabadie A, Gerhardt MF, Jacquemin E. SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect. J Hepatol. 2004 Apr;40(4):716-8. PMID:15030995 doi:10.1016/j.jhep.2003.12.024
↑ Drury JE, Di Costanzo L, Penning TM, Christianson DW. Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex. J Biol Chem. 2009 Jul 24;284(30):19786-90. Epub 2009 Jun 10. PMID:19515843 doi:10.1074/jbc.C109.016931

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3g1r"

@@ Line 3: / Line 3: @@
 <StructureSection load='3g1r' size='340' side='right'caption='[[3g1r]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3g1r]] 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=3G1R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G1R FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3g1r]] 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=3G1R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G1R FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FIT:(4AR,4BS,6AS,7S,9AS,9BS,11AR)-N-TERT-BUTYL-4A,6A-DIMETHYL-2-OXO-2,4A,4B,5,6,6A,7,8,9,9A,9B,10,11,11A-TETRADECAHYDRO-1H-INDENO[5,4-F]QUINOLINE-7-CARBOXAMIDE'>FIT</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]] 1.701&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FIT:(4AR,4BS,6AS,7S,9AS,9BS,11AR)-N-TERT-BUTYL-4A,6A-DIMETHYL-2-OXO-2,4A,4B,5,6,6A,7,8,9,9A,9B,10,11,11A-TETRADECAHYDRO-1H-INDENO[5,4-F]QUINOLINE-7-CARBOXAMIDE'>FIT</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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=3g1r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g1r OCA], [https://pdbe.org/3g1r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g1r RCSB], [https://www.ebi.ac.uk/pdbsum/3g1r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g1r ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 39: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Christianson, D W]]
+[[Category: Christianson DW]]
-[[Category: Costanzo, L Di]]
+[[Category: Di Costanzo L]]
-[[Category: Drury, J E]]
+[[Category: Drury JE]]
-[[Category: Penning, T M]]
+[[Category: Penning TM]]
-[[Category: Bile acid catabolism]]
-[[Category: Cytoplasm]]
-[[Category: Disease mutation]]
-[[Category: Finasteride complex]]
-[[Category: Intrahepatic cholestasis]]
-[[Category: Lipid metabolism]]
-[[Category: Nadp]]
-[[Category: Oxidoreductase]]
-[[Category: Steroid metabolism]]

3g1r

From Proteopedia

Current revision

Crystal structure of human liver 5beta-reductase (AKR1D1) in complex with NADP and Finasteride. Resolution 1.70 A

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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