4XO6

Crystal structure of human 3-alpha hydroxysteroid dehydrogenase type 3 in complex with NADP+, 5alpha-androstan-3,17-dione and (3beta, 5alpha)-3-hydroxyandrostan-17-one

Summary for 4XO6

• Entry DOI: 10.2210/pdb4xo6/pdb
• Related: 4L1W 4L1X 4XO7
• Descriptor: Aldo-keto reductase family 1 member C2, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5ALPHA-ANDROSTAN-3,17-DIONE, ... (8 entities in total)
• Functional Keywords: alpha-beta barrel, human 3-alpha hds3, akr, akr1c2, aldo-keto reductase, nadph, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 76386.76

Authors

Zhang, B.,Hu, X.-J.,Lin, S.-X. (deposition date: 2015-01-16, release date: 2016-02-17, Last modification date: 2024-02-28)

Primary citation

Zhang, B.,Hu, X.J.,Wang, X.Q.,Theriault, J.F.,Zhu, D.W.,Shang, P.,Labrie, F.,Lin, S.X.
Human 3 alpha-hydroxysteroid dehydrogenase type 3: structural clues of 5 alpha-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth.
Biochem.J., 473:1037-1046, 2016

PubMed Abstract: 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.

PubMed: 26929402
DOI: 10.1042/BCJ20160083

Experimental method

X-RAY DIFFRACTION (1.2 Å)