The RNA-binding protein La-related protein 1 (LARP1) plays a central role in ribosome biosynthesis. Its C-terminal DM15 region binds the 7-methylguanosine (m7G) cap and 5' terminal oligopyrimidine (TOP) motif characteristic of transcripts encoding ribosomal proteins and translation factors. Under the control of mammalian target of rapamycin complex 1 (mTORC1), LARP1 regulates translation of these transcripts. Characterizing the dynamics of DM15-TOP recognition is essential to understanding this fundamental biological process. We use molecular dynamics simulations, biophysical assays, and X-ray crystallography to reveal the mechanism of DM15 binding to TOP transcripts. Residues C-terminal to the m7G-binding site play important roles in cap recognition. Furthermore, we show that the unusually static pocket that recognizes the +1 cytosine characteristic of TOP transcripts drives binding specificity. Finally, we demonstrate that the DM15 pockets involved in TOP-specific m7GpppC-motif recognition are likely druggable. Collectively, these studies suggest unique opportunities for further pharmacological development.

中文翻译：

---

捕获 TOP mRNA 与 LARP1 结合的潜在机制。

RNA 结合蛋白 La 相关蛋白 1 (LARP1) 在核糖体生物合成中起核心作用。其 C 末端 DM15 区域结合编码核糖体蛋白和翻译因子的转录本的 7-甲基鸟苷 (m7G) 帽和 5' 末端寡嘧啶 (TOP) 基序特征。在雷帕霉素复合物 1 (mTORC1) 的哺乳动物靶标的控制下，LARP1 调节这些转录物的翻译。表征 DM15-TOP 识别的动力学对于理解这一基本生物过程至关重要。我们使用分子动力学模拟、生物物理分析和 X 射线晶体学来揭示 DM15 与 TOP 转录物结合的机制。m7G 结合位点的 C 末端残基在帽识别中起重要作用。此外，我们表明，识别 TOP 转录物的 +1 胞嘧啶特征的异常静态口袋驱动结合特异性。最后，我们证明了参与 TOP 特异性 m7GpppC 基序识别的 DM15 口袋可能是可药用的。总的来说，这些研究表明了进一步药理学发展的独特机会。