Author(s)

Tang Li¹, Daowei Zhu¹, Fernand Labrie², Shengxiang Lin¹

¹CHU de Quebec Research Center and Department of Molecular Medicine, Laval University, Quebec City, Canada.
²EndoCeutics Inc., Quebec City, Canada.

Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17β-estradiol (E2) from estrone (E1) in the ovary and peripheral tissues, playing a pivotal role in the progression of estrogen-dependent diseases. N-n-Butyl-N-methyl-ll-(16'α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl)undecanamide (EM-139) was previously described as a dual-site inhibitor that can inhibit 17β-HSD1 transforming E1 into E2 and also inhibit estrogen receptor. In the present report, we describe the co-crystallization of EM-139 with 17β-HSD1 as well as the analysis of the three-dimensional structure of the enzyme/inhibitor complex. The crystal is grown under similar condition as native crystals, whereas the space group is changed to I121 never observed in other 17β-HSD1 crystals before. The steroidal moiety of the bound EM-139 molecule has shown a binding pattern similar to E2 in the E2 binary complex. The O-3 of the inhibitor develops hydrogen bonds with residues His²²¹ and Glu²⁸², whereas the O-17 makes hydrogen bonds with Ser¹⁴² and Tyr¹⁵⁵. The bulky 7α-alkyl moiety of the inhibitor, which is essential for its anti-estrogenic activity but cannot be defined in the electron density, may compromise the inhibitory effect of EM-139 to 17β-HSD1. Moreover, the 16α-Cl atom shows no obvious interaction with surrounding residues. The atomic level understanding of the inhibitory mechanism of EM-139 provides important information for the inhibitor design of 17β-HSD1, which will facilitate future development of more potent and selective inhibitors of the enzyme for therapeutic purposes.

17β-HSD1, Inhibitor, Complex Structure, Estrogen-Dependent Diseases

Li, T. , Zhu, D. , Labrie, F. and Lin, S. (2018) Crystal Structures of Human 17β-Hydroxysteroid Dehydrogenase Type 1 Complexed with the Dual-Site Inhibitor EM-139. Health, 10, 1079-1089. doi: 10.4236/health.2018.108081.