Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
IUBMB Life. 2019 Aug;71(8):1167-1180. doi: 10.1002/iub.2098. Epub 2019 Jun 17.
T-box riboswitches are a widespread class of structured noncoding RNAs in Gram-positive bacteria that regulate the expression of amino acid-related genes. They form negative feedback loops to maintain steady supplies of aminoacyl-transfer RNAs (tRNAs) to the translating ribosomes. T-box riboswitches are located in the 5' leader regions of mRNAs that they regulate and directly bind to their cognate tRNA ligands. T-boxes further sense the aminoacylation state of the bound tRNAs and, based on this readout, regulate gene expression at the level of transcription or translation. T-box riboswitches consist of two conserved domains-a 5' Stem I domain that is involved in specific tRNA recognition and a 3' antiterminator/antisequestrator (or discriminator) domain that senses the amino acid on the 3' end of the bound tRNA. Interaction of the 3' end of an uncharged but not charged tRNA with a thermodynamically weak discriminator domain stabilizes it to promote transcription readthrough or translation initiation. Recent biochemical, biophysical, and structural studies have provided high-resolution insights into the mechanism of tRNA recognition by Stem I, several structural models of full-length T-box-tRNA complexes, mechanism of amino acid sensing by the antiterminator domain, as well as kinetic details of tRNA binding to the T-box riboswitches. In addition, translation-regulating T-box riboswitches have been recently characterized, which presented key differences from the canonical transcriptional T-boxes. Here, we review the recent developments in understanding the T-box riboswitch mechanism that have employed various complementary approaches. Further, the regulation of multiple essential genes by T-boxes makes them very attractive drug targets to combat drug resistance. The recent progress in understanding the biochemical, structural, and dynamic aspects of the T-box riboswitch mechanism will enable more precise and effective targeting with small molecules. © 2019 IUBMB Life, 2019 © 2019 IUBMB Life, 71(8):1167-1180, 2019.
T 盒核糖体开关是革兰氏阳性细菌中广泛存在的一类结构非编码 RNA，可调节与氨基酸相关的基因表达。它们形成负反馈回路，以维持氨酰基转移 RNA（tRNA）向翻译核糖体的稳定供应。T 盒核糖体开关位于它们调节的 mRNA 的 5' 前导区，并直接与它们的同源 tRNA 配体结合。T 盒进一步感知结合 tRNA 的氨酰化状态，并根据该读数在转录或翻译水平上调节基因表达。T 盒核糖体开关由两个保守结构域组成 - 涉及特定 tRNA 识别的 5' Stem I 结构域和 3' 终止子/隔离子（或鉴别器）结构域，它感知结合 tRNA 3' 末端的氨基酸。未被负载但未被负载的 tRNA 的 3' 末端与热力学上较弱的鉴别器结构域的相互作用稳定了它，以促进转录通读或翻译起始。最近的生化、生物物理和结构研究为 Stem I 识别 tRNA 的机制、全长 T 盒-tRNA 复合物的几个结构模型、终止子结构域对氨基酸的感应机制以及 tRNA 与 T 盒核糖体开关结合的动力学细节提供了高分辨率的见解。此外，最近还对翻译调节 T 盒核糖体开关进行了表征，这与典型的转录 T 盒有很大的不同。在这里，我们回顾了近年来在理解 T 盒核糖体开关机制方面的最新进展，这些进展采用了各种互补的方法。此外，T 盒对多个必需基因的调节使它们成为对抗耐药性的极具吸引力的药物靶点。对 T 盒核糖体开关机制的生化、结构和动态方面的理解的最新进展将使小分子的靶向更精确和有效。
