Metabolite-protein interactions control a wide range of cellular processes. One prominent example is the allosteric network that regulates the activity of metabolic enzymes to ensure that the cell controls the biochemical reactions and maintain homeostasis. In bacteria this network not only includes metabolic enzymes but expands to proteins that act on gene expression such as the lac repressor whose DNA-binding activity is inhibited by the metabolite allolactose. Similar mechanisms, in which a metabolite-protein interaction regulates the activity of RNA binding proteins, have also been reported in mammals for individual cases. However, it is not clear how prevalent these mechanisms are in mammalian cells. Here, we generalized the limited-proteolysis mass spectrometry (LiP-MS) structural proteomics method to study the crosstalk between metabolite-protein and nucleic acid-protein interactions. Our results provide evidence that ATP binds to RNA-binding domains and that Acetyl-CoA interacts with the DNA-damage- repair complex DNA-PK. We examine how ATP affects RNA binding and how Acetyl- CoA affects the DNA-PK complex activity, highlighting the importance of metabolism in controlling cellular programs.