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
4XO6 の概要
エントリーDOI | 10.2210/pdb4xo6/pdb |
関連するPDBエントリー | 4L1W 4L1X 4XO7 |
分子名称 | Aldo-keto reductase family 1 member C2, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5ALPHA-ANDROSTAN-3,17-DIONE, ... (8 entities in total) |
機能のキーワード | alpha-beta barrel, human 3-alpha hds3, akr, akr1c2, aldo-keto reductase, nadph, oxidoreductase |
由来する生物種 | Homo sapiens (Human) |
タンパク質・核酸の鎖数 | 2 |
化学式量合計 | 76386.76 |
構造登録者 | |
主引用文献 | 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 Cited by 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: 26929402DOI: 10.1042/BCJ20160083 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (1.2 Å) |
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