Nishide Goro, Ishibashi Tomoka, Lim Keesiang, Qiu Yujia, Hazawa Masaharu, Matsushima Ayami, Wong Richard W
Division of Nano Life Science in the Graduate School of Frontier Science Initiative, WISE Program for Nano-Precision Medicine, Science and Technology, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty of Science, Kyushu University, Fukuoka 819-0395, Japan.
ACS Nano. 2025 Apr 29;19(16):15395-15410. doi: 10.1021/acsnano.4c14943. Epub 2025 Apr 18.
Estrogen receptor α (ERα) is pivotal in gene regulation, particularly in estrogen-responsive cancers. However, the full-length molecular dynamic structure of ERα remains elusive. In this study, we employ high-speed atomic force microscopy (HS-AFM) to visualize ERα interactions with the estrogen response element (ERE) under both ligand-present and ligand-absent conditions. ERα binds to ERE even in the absence of estrogen, although the presence of the ligand significantly enhances binding precision and stability. Our real-time, high-resolution HS-AFM imaging captures ERα structural transitions from monomeric to dimeric forms, elucidating the molecular mechanisms by which estrogen modulates DNA-binding specificity. Based on these findings, we propose a ligand-induced dimerization (LID) model, wherein estrogen facilitates the optimal loading of ERα onto DNA. These insights deepen our understanding of hormone signaling in cancer and hold promise for the development of future therapeutic strategies targeting hormone-related malignancies.
雌激素受体α（ERα）在基因调控中起关键作用，尤其是在雌激素反应性癌症中。然而，ERα的全长分子动力学结构仍然难以捉摸。在本研究中，我们采用高速原子力显微镜（HS-AFM）在有配体和无配体条件下观察ERα与雌激素反应元件（ERE）的相互作用。即使在没有雌激素的情况下，ERα也能与ERE结合，尽管配体的存在显著提高了结合的精确性和稳定性。我们的实时、高分辨率HS-AFM成像捕捉到了ERα从单体形式到二聚体形式的结构转变，阐明了雌激素调节DNA结合特异性的分子机制。基于这些发现，我们提出了一种配体诱导二聚化（LID）模型，其中雌激素促进ERα在DNA上的最佳负载。这些见解加深了我们对癌症中激素信号传导的理解，并为未来针对激素相关恶性肿瘤的治疗策略的开发带来了希望。
