Saon Md Sharear, Douds Catherine A, Veenis Andrew J, Pearson Ashley N, Yennawar Neela H, Bevilacqua Philip C
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, United States.
Center for RNA Molecular Biology, Pennsylvania State University, University Park, PA 16802, United States.
Nucleic Acids Res. 2025 Jul 19;53(14). doi: 10.1093/nar/gkaf575.
RNA can serve as an enzyme, small molecule sensor, and vaccine, and it may have been a conduit for the origin of life. Despite these profound functions, RNA is thought to have limited molecular diversity. A pressing question is whether RNA can adopt novel molecular states that enhance its function. Covalent modifications of RNA have been demonstrated to augment biological function, but much less is known about non-covalent alterations such as novel protonated or tautomeric forms. Conventionally, a G•U wobble has the U located in the major groove. We used a cheminformatic approach to identify four structural families of shifted G•U wobbles in which the G instead resides in the major groove, which requires alternative tautomeric states of either base, or an anionic state of the U. We provide experimental support for these shifted G•U wobbles via the unconventional in vivo reactivity of the U with dimethylsulfate (DMS). These shifted wobbles may play functional roles and could serve as drug targets, as they are common in Bacteria and chloroplasts, but underrepresented in Eukaryotes and Archaea. Our cheminformatics approach can be applied to identify alternative protonation states in other RNA motifs, as well as in DNA and proteins.
RNA可以充当酶、小分子传感器和疫苗，并且它可能是生命起源的一个渠道。尽管有这些重要功能，但人们认为RNA的分子多样性有限。一个紧迫的问题是RNA是否能够采用增强其功能的新分子状态。RNA的共价修饰已被证明可增强生物学功能，但对于诸如新的质子化或互变异构形式等非共价改变的了解要少得多。传统上，G•U摆动碱基对中的U位于大沟中。我们使用化学信息学方法鉴定了四种移位G•U摆动碱基对的结构家族，其中G位于大沟中，这需要碱基的互变异构状态或U的阴离子状态。我们通过U与硫酸二甲酯（DMS）的非常规体内反应性为这些移位的G•U摆动碱基对提供了实验支持。这些移位的摆动碱基对可能发挥功能作用，并可作为药物靶点，因为它们在细菌和叶绿体中很常见，但在真核生物和古细菌中代表性不足。我们的化学信息学方法可用于识别其他RNA基序以及DNA和蛋白质中的替代质子化状态。
