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 通过结合调控 DNA 位点和干扰其他因子的功能，在前列腺癌和尤文肉瘤的肿瘤发生中起关键作用。光神霉素 (MTM) 是一种抗癌、DNA 结合的天然产物，通过未知机制发挥有效的 ERG 和 FLI1 拮抗剂的作用。我们提出了 ERG/FLI1 的 DNA 结合域 (DBD) 的一系列晶体结构，最终形成了 ERG/FLI1 DBD、转录因子 Runx2、核心结合因子β (Cbfβ) 和DNA 增强子位点上的 MTM，以及使用 MTM 及其类似物的支持 DNA 结合研究。总之，这些数据提供了对 ERG 和 FLI1 交易的变构机制及其被 MTM 类似物破坏的洞察力。