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4l1w

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Crystal Structuer of Human 3-alpha Hydroxysteroid Dehydrogenase Type 3 in Complex with NADP+ and Progesterone

Structural highlights

4l1w 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 2.2Å
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]

Publication Abstract from PubMed

Human 3-alpha hydroxysteroid dehydrogenase type 3 (3alpha-HSD3) has an essential role in the inactivation of 5alpha-dihydrotestosterone (DHT). Notably, human 3alpha-HSD3 shares 97.8% sequence identity with human 20-alpha hydroxysteroid dehydrogenase (20alpha-HSD) and there is only one amino acid difference (residue 54) that is located in their steroid binding pockets. However, 20alpha-HSD displays a distinctive ability in transforming progesterone to 20alpha-hydroxy-progesterone (20alpha-OHProg). In this study, to understand the role of residue 54 in the steroid binding and discrimination, the V54L mutation in human 3alpha-HSD3 has been created. We have solved two crystal structures of the 3alpha-HSD3.NADP(+).Progesterone complex and the 3alpha-HSD3 V54L.NADP(+).progesterone complex. Interestingly, progesterone adopts two different binding modes to form complexes within the wild type enzyme, with one binding mode similar to the orientation of a bile acid (ursodeoxycholate) in the reported ternary complex of human 3alpha-HSD3.NADP(+).ursodeoxycholate and the other binding mode resembling the orientation of 20alpha-OHProg in the ternary complex of human 20alpha-HSD.NADP(+).20alpha-OHProg. However, the V54L mutation directly restricts the steroid binding modes to a unique one, which resembles the orientation of 20alpha-OHProg within human 20alpha-HSD. Furthermore, the kinetic study has been carried out. The results show that the V54L mutation significantly decreases the 3alpha-HSD activity for the reduction of DHT, while this mutation enhances the 20alpha-HSD activity to convert progesterone.

Human 3-alpha hydroxysteroid dehydrogenase type 3 (3alpha-HSD3): The V54L mutation restricting the steroid alternative binding and enhancing the 20alpha-HSD activity.,Zhang B, Zhu DW, Hu XJ, Zhou M, Shang P, Lin SX J Steroid Biochem Mol Biol. 2014 May;141:135-43. doi:, 10.1016/j.jsbmb.2014.01.003. Epub 2014 Jan 13. PMID:24434280^[3]

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

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
↑ Zhang B, Zhu DW, Hu XJ, Zhou M, Shang P, Lin SX. Human 3-alpha hydroxysteroid dehydrogenase type 3 (3alpha-HSD3): The V54L mutation restricting the steroid alternative binding and enhancing the 20alpha-HSD activity. J Steroid Biochem Mol Biol. 2014 May;141:135-43. doi:, 10.1016/j.jsbmb.2014.01.003. Epub 2014 Jan 13. PMID:24434280 doi:http://dx.doi.org/10.1016/j.jsbmb.2014.01.003

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4l1w"

Categories: Homo sapiens | Large Structures | Hu X-J | Lin S-X | Zhang B

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4l1w]] 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=4L1W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L1W FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=STR:PROGESTERONE'>STR</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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=STR:PROGESTERONE'>STR</scene></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=4l1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l1w OCA], [https://pdbe.org/4l1w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l1w RCSB], [https://www.ebi.ac.uk/pdbsum/4l1w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l1w ProSAT]</span></td></tr>
 </table>

4l1w

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Current revision

Crystal Structuer of Human 3-alpha Hydroxysteroid Dehydrogenase Type 3 in Complex with NADP+ and Progesterone

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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