5O7C

17beta-hydroxysteroid dehydrogenase 14 variant T205 in complex with a non-steroidal quinoline based inhibitor

5O7C の概要

• エントリーDOI: 10.2210/pdb5o7c/pdb
• 分子名称: 17-beta-hydroxysteroid dehydrogenase 14, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, SODIUM ION, ... (6 entities in total)
• 機能のキーワード: non-steroidal inhibitor, 17beta-hsd14, quinoline based inhibitors, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29841.58

構造登録者

Bertoletti, N.,Braun, F.,Heine, A.,Klebe, G.,Marchais-Oberwinkler, S. (登録日: 2017-06-08, 公開日: 2018-06-06, 最終更新日: 2024-11-13)

主引用文献

Braun, F.,Bertoletti, N.,Moller, G.,Adamski, J.,Frotscher, M.,Guragossian, N.,Madeira Girio, P.A.,Le Borgne, M.,Ettouati, L.,Falson, P.,Muller, S.,Vollmer, G.,Heine, A.,Klebe, G.,Marchais-Oberwinkler, S.
Structure-based design and profiling of novel 17 beta-HSD14 inhibitors.
Eur J Med Chem, 155:61-76, 2018

PubMed Abstract: The human enzyme 17β-hydroxysteroid dehydrogenase 14 (17β-HSD14) oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD as cofactor. However, the physiological role of the enzyme remains unclear. We recently described the first class of nonsteroidal inhibitors for this enzyme with compound 1 showing a high 17β-HSD14 inhibitory activity. Its crystal structure was used as starting point for a structure-based optimization in this study. The goal was to develop a promising chemical probe to further investigate the enzyme. The newly designed compounds revealed mostly very high inhibition of the enzyme and for seven of them the crystal structures of the corresponding inhibitor-enzyme complexes were resolved. The crystal structures disclosed that a small change in the substitution pattern of the compounds resulted in an alternative binding mode for one inhibitor. The profiling of a set of the most potent inhibitors identified 13 (K = 9 nM) with a good selectivity profile toward three 17β-HSDs and the estrogen receptor alpha. This inhibitor displayed no cytotoxicity, good solubility, and auspicious predicted bioavailability. Overall, 13 is a highly interesting 17β-HSD14 inhibitor, which might be used as chemical probe for further investigation of the target enzyme.

PubMed: 29859505
DOI: 10.1016/j.ejmech.2018.05.029

実験手法

X-RAY DIFFRACTION (1.6 Å)