文章基本信息

标题：Crystal Structures of Human 17β-Hydroxysteroid Dehydrogenase Type 1 Complexed with the Dual-Site Inhibitor EM-139
本地全文：下载
作者：Tang Li ; Daowei Zhu ; Fernand Labrie 等
期刊名称：Health
印刷版ISSN：1949-4998
电子版ISSN：1949-5005
出版年度：2018
卷号：10
期号：08
页码：1079-1089
DOI：10.4236/health.2018.108081
语种：English
出版社：Scientific Research Publishing
摘要：Human 17 β -hydroxysteroid dehydrogenase type 1 (17 β -HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17 β -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 17 β -HSD1 transforming E1 into E2 and also inhibit estrogen receptor. In the present report, we describe the co-crystallization of EM-139 with 17 β -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 17 β -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 7 α -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 17 β -HSD1. Moreover, the 16 α -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 17 β -HSD1, which will facilitate future development of more potent and selective inhibitors of the enzyme for therapeutic purposes.
关键词：17β-HSD1;Inhibitor;Complex Structure;Estrogen-Dependent Diseases