4l1w | pdb_00004l1w
Crystal Structuer of Human 3-alpha Hydroxysteroid Dehydrogenase Type 3 in Complex with NADP+ and Progesterone
Structural highlights
DiseaseAK1C2_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] FunctionAK1C2_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 PubMedHuman 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. See AlsoReferences
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