During the last decade, riboswitches emerged as new small-molecule sensing RNA in bacteria. Thiamine pyrophosphate (TPP) riboswitch is widely distributed and occurs in plants, bacteria, fungi, and archaea. Extensive biochemical, structural, and genetic studies have been carried out to elucidate the recognition mechanism of TPP riboswitches. However, a comprehensive report summarizing all information on recognition principles and newly designed ligands for TPP riboswitch is scarce in the literature. This review gives a comprehensive understanding of the TPP riboswitch's structure, mechanism, and methods applied to design ligands for the TPP riboswitch. The ligand-bound TPP riboswitch was studied with various experimental and theoretical techniques to elucidate the conformational dynamics. The mutation studies shed light on the significance of pyrimidine sensing helix for the binding of ligands. Further, the structure–activity relationship study and fragment-based approach lead to the development of ligands with K_d values at the sub-micromolar level. However, there is a need to design more potent inhibitors for TPP riboswitch for therapeutic applications. The recent advancements in ligand design highlight the TPP riboswitch as a promising target for developing new antibiotics.

中文翻译：

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探索硫胺素焦磷酸核糖开关的结构、功能，设计抗菌活性小分子

在过去十年中，核糖开关作为细菌中新的小分子传感 RNA 出现。焦磷酸硫胺素（TPP）核糖开关广泛分布并存在于植物、细菌、真菌和古细菌中。为了阐明 TPP 核糖开关的识别机制，已经进行了广泛的生化、结构和遗传学研究。然而，文献中缺乏总结有关识别原理和新设计的 TPP 核糖开关配体的所有信息的综合报告。本综述全面了解了 TPP 核糖开关的结构、机制以及用于设计 TPP 核糖开关配体的方法。通过各种实验和理论技术研究了配体结合的 TPP 核糖开关，以阐明构象动力学。突变研究揭示了嘧啶传感螺旋对于配体结合的重要性。此外，结构-活性关系研究和基于片段的方法导致了 K 配体的开发_d值在亚微摩尔水平。然而，需要为 TPP 核糖开关设计更有效的抑制剂以用于治疗应用。配体设计的最新进展凸显了 TPP 核糖开关作为开发新抗生素的有希望的目标。