Human 3α-hydroxysteroid dehydrogenase type 3: structural clues of 5α-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth
| العنوان: | Human 3α-hydroxysteroid dehydrogenase type 3: structural clues of 5α-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth |
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| المؤلفون: | Bo Zhang, Fernand Labrie, Dao-Wei Zhu, Peng Shang, Xiao-Qiang Wang, Sheng-Xiang Lin, Jean-François Thériault, Xiao-Jian Hu |
| المصدر: | Biochemical Journal. 473:1037-1046 |
| بيانات النشر: | Portland Press Ltd., 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Down-Regulation, Dehydrogenase, Plasma protein binding, Epiandrosterone, Biology, Biochemistry, Protein Structure, Secondary, 03 medical and health sciences, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific), 0302 clinical medicine, X-Ray Diffraction, Oxidoreductase, Humans, Binding site, Molecular Biology, chemistry.chemical_classification, Binding Sites, Cell growth, Dihydrotestosterone, Cell Biology, Growth Inhibitors, 030104 developmental biology, Enzyme, chemistry, 030220 oncology & carcinogenesis, MCF-7 Cells, Crystallization, Protein Binding |
| الوصف: | Human 3α-HSD3 (3α-hydroxysteroid dehydrogenase type 3) plays an essential role in the inactivation of the most potent androgen 5α-DHT (5α-dihydrotestosterone). The present study attempts to obtain the important structure of 3α-HSD3 in complex with 5α-DHT and to investigate the role of 3α-HSD3 in breast cancer cells. We report the crystal structure of human 3α-HSD3·NADP+·A-dione (5α-androstane-3,17-dione)/epi-ADT (epiandrosterone) complex, which was obtained by co-crystallization with 5α-DHT in the presence of NADP+. Although 5α-DHT was introduced during the crystallization, oxidoreduction of 5α-DHT occurred. The locations of A-dione and epi-ADT were identified in the steroid-binding sites of two 3α-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 5α-DHT reverse binding in the enzyme with the generation of different products. Moreover, we report the crystal structure of the 3α-HSD3·NADP+·4-dione (4-androstene-3,17-dione) complex. When a specific siRNA (100 nM) was used to suppress 3α-HSD3 expression without interfering with 3α-HSD4, which shares a highly homologous active site, the 5α-DHT concentration increased, whereas MCF7 cell growth was suppressed. The present study provides structural clues for 5α-DHT reverse binding within 3α-HSD3, and demonstrates for the first time that down-regulation of 3α-HSD3 decreases MCF7 breast cancer cell growth. |
| تدمد: | 1470-8728 0264-6021 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d1dcdf559700f223e9c84a66918ec1cTest https://doi.org/10.1042/bcj20160083Test |
| رقم الانضمام: | edsair.doi.dedup.....6d1dcdf559700f223e9c84a66918ec1c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14708728 02646021 |
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