View source for 4l1x


==Crystal Structuer of Human 3-alpha Hydroxysteroid Dehydrogenase Type 3 V54L Mutant in Complex with NADP+ and Progesterone==
<StructureSection load='4l1x' size='340' side='right'caption='[[4l1x]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4l1x]] 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=4L1X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L1X FirstGlance]. <br>
</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&#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=4l1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l1x OCA], [https://pdbe.org/4l1x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l1x RCSB], [https://www.ebi.ac.uk/pdbsum/4l1x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l1x ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/AK1C2_HUMAN AK1C2_HUMAN] Defects in AKR1C2 are a cause of 46,XY sex reversal type 8 (SRXY8) [MIM:[https://omim.org/entry/614279 614279]. A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.<ref>PMID:21802064</ref> 
== Function ==
[https://www.uniprot.org/uniprot/AK1C2_HUMAN 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.<ref>PMID:8573067</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:24434280</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4l1x" style="background-color:#fffaf0;"></div>

==See Also==
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hu X-J]]
[[Category: Lin S-X]]
[[Category: Zhang B]]