Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Structure. 2021 May 6;29(5):404-412.e4. doi: 10.1016/j.str.2020.11.012. Epub 2020 Dec 3.
ETS family transcription factors of ERG and FLI1 play a key role in oncogenesis of prostate cancer and Ewing sarcoma by binding regulatory DNA sites and interfering with function of other factors. Mithramycin (MTM) is an anti-cancer, DNA binding natural product that functions as a potent antagonist of ERG and FLI1 by an unknown mechanism. We present a series of crystal structures of the DNA binding domain (DBD) of ERG/FLI1 culminating in a structure of a high-order complex of the ERG/FLI1 DBD, transcription factor Runx2, core-binding factor beta (Cbfβ), and MTM on a DNA enhancer site, along with supporting DNA binding studies using MTM and its analogues. Taken together, these data provide insight into allosteric mechanisms underlying ERG and FLI1 transactions and their disruption by MTM analogues.
ETS 家族转录因子 ERG 和 FLI1 通过结合调节性 DNA 位点并干扰其他因子的功能，在前列腺癌和尤文肉瘤的发生中发挥关键作用。米托蒽醌（MTM）是一种抗癌的 DNA 结合天然产物，通过未知机制作为 ERG 和 FLI1 的有效拮抗剂。我们展示了一系列 ERG/FLI1 的 DNA 结合结构域（DBD）的晶体结构，最终形成了 ERG/FLI1 DBD、转录因子 Runx2、核心结合因子β（Cbfβ）和 MTM 结合在 DNA 增强子位点的高阶复合物结构，以及使用 MTM 及其类似物进行的支持性 DNA 结合研究。这些数据共同提供了 ERG 和 FLI1 相互作用及其被 MTM 类似物破坏的变构机制的见解。
