Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden.
Sci Rep. 2023 Sep 26;13(1):16125. doi: 10.1038/s41598-023-43244-1.
Transcription factors (TFs) regulate eukaryotic transcription through selective DNA-binding, can also specifically interact with RNA, which may present another layer of transcriptional control. The mechanisms of the TFs-DNA recognition are often well-characterised, while the details of TFs-RNA complexation are less understood. Here we investigate the dual recognition mechanism of the glucocorticoid receptor (GR), which interacts with similar affinities with consensus DNA and diverse RNA hairpin motifs but discriminates against uniform dsRNA. Using atomic molecular dynamics simulations, we demonstrate that the GR binding to nucleic acids requires a wide and shallow groove pocket. The protein effectively moulds its binding site within DNA major groove, which enables base-specific interactions. Contrary, the GR binding has little effect on the grooves geometry of RNA systems, most notably in uniform dsRNA. Instead, a hairpin motif in RNA yields a wide and shallow major groove pocket, allowing the protein to anchor itself through nonspecific electrostatic contacts with RNA backbone. Addition of a bulge increases RNA hairpin flexibility, which leads to a greater number of GR-RNA contacts and, thus, higher affinity. Thus, the combination of structural motifs defines the GR-RNA selective binding: a recognition mechanism, which may be shared by other zinc finger TFs.
转录因子 (TFs) 通过选择性的 DNA 结合来调节真核转录，也可以与 RNA 特异性相互作用，这可能提供了另一种转录控制的层次。TFs-DNA 识别的机制通常得到很好的描述，而 TFs-RNA 复合物的细节则了解较少。在这里，我们研究了糖皮质激素受体 (GR) 的双重识别机制，它与保守的 DNA 和各种 RNA 发夹基序具有相似的亲和力，但对均匀的 dsRNA 具有区分能力。使用原子分子动力学模拟，我们证明了 GR 与核酸的结合需要一个宽而浅的沟袋。该蛋白质有效地在 DNA 大沟内塑造其结合位点，从而实现碱基特异性相互作用。相反，GR 结合对 RNA 系统的沟几何形状几乎没有影响，尤其是在均匀的 dsRNA 中。相反，RNA 中的发夹基序产生宽而浅的大沟袋，允许蛋白质通过与 RNA 骨架的非特异性静电接触来锚定自身。引入突环增加了 RNA 发夹的灵活性，从而导致更多的 GR-RNA 接触，因此亲和力更高。因此，结构基序的组合定义了 GR-RNA 的选择性结合：这可能是其他锌指 TFs 共有的识别机制。
