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首页> 外文期刊>Biochemistry >Nuclease-Resistant c-di-AMP Derivatives That Differentially Recognize RNA and Protein Receptors
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Nuclease-Resistant c-di-AMP Derivatives That Differentially Recognize RNA and Protein Receptors

机译：差异识别 RNA 和蛋白质受体的抗核酸酶 c-di-AMP 衍生物

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The ability of bacteria to sense environmental cues and adapt is essential for their survival. The use of second messenger signaling molecules to translate these cues into a physiological response is a common mechanism employed by bacteria. The second messenger 3'-5'-cyclic diadenosine monophosphate (c-di-AMP) has been linked to a diverse set of biological processes involved in maintaining cell viability and homeostasis, as well as pathogenicity. A complex network of both protein and RNA receptors inside the cell activates specific pathways and mediates phenotypic outputs in response to c-di-AMP. Structural analysis of these RNA and protein receptors has revealed the different recognition elements employed by these effectors to bind the same small molecule. Herein, using a series of c-di-AMP analogues, we probed the interactions made with a riboswitch and a phosphodiesterase protein to identify the features important for c-di-AMP binding and recognition. We found that the ydaO riboswitch binds c-di-AMP in two discrete sites with near identical affinity and a Hill coefficient of 1.6. The ydaO riboswitch distinguishes between c-di-AMP and structurally related second messengers by discriminating against an amine at the C2 position more than a carbonyl at the C6 position. We also identified phosphate modified analogues that bind both the ydaO RNA and GdpP protein with high affinity, whereas symmetrically modified ribose analogues exhibited a substantial decrease in ydaO affinity but retained high affinity for GdpP. These ligand modifications resulted in increased resistance to enzyme-catalyzed hydrolysis by the GdpP enzyme. Together, these data suggest that these c-di-AMP analogues could be useful as chemical tools to specifically target subsections of second-messenger signaling pathways.
机译：细菌感知环境线索和适应的能力对其生存至关重要。使用第二信使信号分子将这些线索转化为生理反应是细菌采用的常见机制。第二信使 3'-5'-环二磷酸二腺苷 （c-di-AMP） 与维持细胞活力和稳态以及致病性的多种生物过程有关。细胞内蛋白质和 RNA 受体的复杂网络激活特定通路并介导响应 c-di-AMP 的表型输出。对这些RNA和蛋白质受体的结构分析揭示了这些效应子用来结合同一小分子的不同识别元件。在此，使用一系列c-di-AMP类似物，我们探测了与核糖开关和磷酸二酯酶蛋白的相互作用，以确定对c-di-AMP结合和识别很重要的特征。我们发现 ydaO 核糖开关在两个离散位点结合 c-di-AMP，亲和力几乎相同，Hill 系数为 1.6。ydaO 核糖开关通过区分 C2 位的胺多于 C6 位的羰基来区分 c-di-AMP 和结构相关的第二信使。我们还鉴定了磷酸盐修饰的类似物，这些类似物以高亲和力结合ydaO RNA和GdpP蛋白，而对称修饰的核糖类似物表现出ydaO亲和力的显着降低，但对GdpP保持高亲和力。这些配体修饰导致对 GdpP 酶催化的酶催化水解的抵抗力增加。总之，这些数据表明，这些c-di-AMP类似物可以作为化学工具，专门靶向第二信使信号通路的亚段。

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