In this project we set-up the methodological framework by showing that structural proteomics can be used to identify new drug targets in human cells. We also figured that analysis of global protein structural responses are more sensitive readouts than classical protein abundance measurements for interrogating activation of biological responses in cells and tissues (Mateus, et. al. MSB 2021). This establishes the methodological background for addressing the scientific questions proposed in this project.
We carried on highlighting the importance of small molecules in modulating intermolecular and intramolecular binding interfaces between multiple proteins (Ruwolt et. al. Current Opinion in structural biology 2023). We also investigated the contribution of post-translational gene regulation in explaining transcriptional memory in Saccharomyces cerevisiae. We showed that the protein subunits of the nuclear exosome (the TRAMP and the NNS complexes) are less active in primed conditions compared to naive conditions. This decrease in protein function is consistent with a relative increase in the expression of genes sensitive to the action of the nuclear exosome. Unexpectedly, there was also a relative decrease in factors involved in cytoplasmic decay. This suggests that changes in the cytoplasmic mRNA decay may contribute to modulate transcriptional memory in yeast (Li et. al. Nature Communications, 2023).
We have also presented a comprehensive workflow to perform structural proteomics experiments to discover proteins interacting with drugs or metabolite (Koudelka et. al. Molecular&Cellular Proteomics, 2025).
