Download MendeleyHuman 3 alpha-hydroxysteroid dehydrogenase type 3: structural clues of 5 alpha-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth.
Zhang, B., Hu, X.J., Wang, X.Q., Theriault, J.F., Zhu, D.W., Shang, P., Labrie, F., Lin, S.X.(2016) Biochem J 473: 1037-1046
- PubMed: 26929402
- DOI: https://doi.org/10.1042/BCJ20160083
- Primary Citation of Related Structures:
4XO6, 4XO7 - PubMed Abstract:
Human 3¦Á-HSD3 (3¦Á-hydroxysteroid dehydrogenase type 3) plays an essential role in the inactivation of the most potent androgen 5¦Á-DHT (5¦Á-dihydrotestosterone). The present study attempts to obtain the important structure of 3¦Á-HSD3 in complex with 5¦Á-DHT and to investigate the role of 3¦Á-HSD3 in breast cancer cells. We report the crystal structure of human 3¦Á-HSD3¡¤NADP(+)¡¤A-dione (5¦Á-androstane-3,17-dione)/epi-ADT (epiandrosterone) complex, which was obtained by co-crystallization with 5¦Á-DHT in the presence of NADP(+) Although 5¦Á-DHT was introduced during the crystallization, oxidoreduction of 5¦Á-DHT occurred. The locations of A-dione and epi-ADT were identified in the steroid-binding sites of two 3¦Á-HSD3 molecules per crystal asymmetric unit. An overlay showed that A-dione and epi-ADT were oriented upside-down and flipped relative to each other, providing structural clues for 5¦Á-DHT reverse binding in the enzyme with the generation of different products. Moreover, we report the crystal structure of the 3¦Á-HSD3¡¤NADP(+)¡¤4-dione (4-androstene-3,17-dione) complex. When a specific siRNA (100 nM) was used to suppress 3¦Á-HSD3 expression without interfering with 3¦Á-HSD4, which shares a highly homologous active site, the 5¦Á-DHT concentration increased, whereas MCF7 cell growth was suppressed. The present study provides structural clues for 5¦Á-DHT reverse binding within 3¦Á-HSD3, and demonstrates for the first time that down-regulation of 3¦Á-HSD3 decreases MCF7 breast cancer cell growth.
Organizational Affiliation:
Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Quebec Research Center (CHUL, CHU) and Laval University, Qu¨¦bec City, Qu¨¦bec, G1V4G2, Canada Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, P.R. China.
