Download MendeleyHuman 3-alpha hydroxysteroid dehydrogenase type 3 (3 alpha-HSD3): The V54L mutation restricting the steroid alternative binding and enhancing the 20 alpha-HSD activity
Zhang, B., Zhu, D.-W., Hu, X.-J., Zhou, M., Shang, P., Lin, S.-X.(2014) J Steroid Biochem Mol Biol 141: 135-143
- PubMed: 24434280
- DOI: https://doi.org/10.1016/j.jsbmb.2014.01.003
- Primary Citation of Related Structures:
4L1W, 4L1X - PubMed Abstract:
Human 3-alpha hydroxysteroid dehydrogenase type 3 (3¦Á-HSD3) has an essential role in the inactivation of 5¦Á-dihydrotestosterone (DHT). Notably, human 3¦Á-HSD3 shares 97.8% sequence identity with human 20-alpha hydroxysteroid dehydrogenase (20¦Á-HSD) and there is only one amino acid difference (residue 54) that is located in their steroid binding pockets. However, 20¦Á-HSD displays a distinctive ability in transforming progesterone to 20¦Á-hydroxy-progesterone (20¦Á-OHProg). In this study, to understand the role of residue 54 in the steroid binding and discrimination, the V54L mutation in human 3¦Á-HSD3 has been created. We have solved two crystal structures of the 3¦Á-HSD3¡¤NADP(+)¡¤Progesterone complex and the 3¦Á-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 3¦Á-HSD3¡¤NADP(+)¡¤ursodeoxycholate and the other binding mode resembling the orientation of 20¦Á-OHProg in the ternary complex of human 20¦Á-HSD¡¤NADP(+)¡¤20¦Á-OHProg. However, the V54L mutation directly restricts the steroid binding modes to a unique one, which resembles the orientation of 20¦Á-OHProg within human 20¦Á-HSD. Furthermore, the kinetic study has been carried out. The results show that the V54L mutation significantly decreases the 3¦Á-HSD activity for the reduction of DHT, while this mutation enhances the 20¦Á-HSD activity to convert progesterone.
Organizational Affiliation:
Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire (CHU) de Quebec Research Center (CHUL) and Laval University, Qu¨¦bec City, Qu¨¦bec G1V4G2, Canada; Key Laboratory for Space Bioscience & Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, PR China.
