1EQU

TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EQUILIN COMPLEXED WITH NADP+

1EQU の概要

• エントリーDOI: 10.2210/pdb1equ/pdb
• 分子名称: PROTEIN (ESTRADIOL 17 BETA-DEHYDROGENASE 1), NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, EQUILIN, ... (4 entities in total)
• 機能のキーワード: hydroxysteroid dehydrogenase, short chain dehydrogenase, reductase, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P14061
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71530.82

構造登録者

Sawicki, M.W.,Erman, M.,Puranen, T.,Vihko, P.,Ghosh, D. (登録日: 1998-12-02, 公開日: 1999-12-02, 最終更新日: 2024-12-25)

主引用文献

Sawicki, M.W.,Erman, M.,Puranen, T.,Vihko, P.,Ghosh, D.
Structure of the ternary complex of human 17beta-hydroxysteroid dehydrogenase type 1 with 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin) and NADP+.
Proc.Natl.Acad.Sci.USA, 96:840-845, 1999

PubMed Abstract: Excess 17beta-estradiol (E2), the most potent of human estrogens, is known to act as a stimulus for the growth of breast tumors. Human estrogenic 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which catalyzes the reduction of inactive estrone (E1) to the active 17beta-estradiol in breast tissues, is a key enzyme responsible for elevated levels of E2 in breast tumor tissues. We present here the structure of the ternary complex of 17beta-HSD1 with the cofactor NADP+ and 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin), an equine estrogen used in estrogen replacement therapy. The ternary complex has been crystallized with a homodimer, the active form of the enzyme, in the asymmetric unit. Structural and kinetic data presented here show that the 17beta-HSD1-catalyzed reduction of E1 to E2 in vitro is specifically inhibited by equilin. The crystal structure determined at 3.0-A resolution reveals that the equilin molecule is bound at the active site in a mode similar to the binding of substrate. The orientation of the 17-keto group with respect to the nicotinamide ring of NADP+ and catalytic residues Tyr-155 and Ser-142 is different from that of E2 in the 17beta-HSD1-E2 complex. The ligand and substrate-entry loop densities are well defined in one subunit. The substrate-entry loop adopts a closed conformation in this subunit. The result demonstrates that binding of equilin at the active site of 17beta-HSD1 is the basis for inhibition of E1-to-E2 reduction by this equine estrogen in vitro. One possible outcome of estrogen replacement therapy in vivo could be reduction of E2 levels in breast tissues and hence the reduced risk of estrogen-dependent breast cancer.

PubMed: 9927655
DOI: 10.1073/pnas.96.3.840

実験手法

X-RAY DIFFRACTION (3 Å)