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Hydroxysteroid dehydrogenases (HSDs) regulate a wide range of physiological processes including reproduction, development and homeostasis. AKR1C1, is a 20α-HSD involved in the conversion of progesterone to 20-hydroxyprogesterone. Increased activity of AKR1C1 in the endometrium and in breast tissues leads to the formation of tumor-promoting metabolites and to the development of endometriosis, breast cancer and endometrial cancer. At present, there are few known inhibitors that specifically bind and inhibit the adverse actions of AKR1C1. Here we present the first crystal structure of AKR1C1 in complex with potent inhibitor 3,5-dichlorosalicylic acid (IC50 = 44 nM). The crystal structure was solved at a resolution of 1.8 Å, with clear electron density corresponding to the inhibitor bound in the active site. The details of the enzyme-inhibitor interactions and selectivity against members of the AKR1C subfamily will also be discussed. The structural information obtained from this study will help speed up the drug design process for the development of more selective and potent compounds that can be used in the treatment of endometriosis and cancer.

Crystal structure and structure-based drug design of HU (histone-like protein) fromM. tuberculosis