Our research is concerned with structural aspects of protein function. We are interested in how proteins interact with other macromolecules or small-molecule ligands, and how these interactions relate to biological function. In this context, we are interested in identifying small-molecule inhibitors of functionally important protein interactions. To pursue these goals we use NMR spectroscopy, computational methods and chemical biology approaches.
The primary focus of our research is on how protein interactions control gene expression. On the one hand, we want to understand how eukaryotic translation initiation factors regulates the fate of cells. In particular, we are interested in the interaction of the cap-binding protein eIF4E with the mRNA cap, the scaffold protein eIF4G, and the regulatory 4E-BPs, and how these interactions are related to cell transformation and apoptosis. To address this, we have identified small-molecule inhibitors of the eIF4E/eIF4G interaction and found that these may have anti-tumor activity. We are also working on other factors involved in eukaryotic translation initiation, such as eIF2, eIF2B, eIF5B, eIF5 and eIF4A. In a related effort we are interested in the regulation of transcriptional activation. We are studying the interaction of transactivation domains of transcriptional activators with components of co-activator complexes, such as the human ARC or the mediator of yeast.
We also seek to understand mechanisms of T-cell function from structural studies of T-cell protein complexes involving CD2, the αβTCR, CD3, proteins that bind cytoplasmic tails of T-cell receptor proteins, or protein involved in signaling pathways, such as calcineurin and NFAT. In addition, we are interested in protein-protein interactions in apoptosis and inhibitors of pro-survival proteins. This includes studies of several anti- and pro-apoptotic proteins located in the cytoplasm or the mitochondrial membrane.
Furthermore, we are interested in developing improved experimental and computational methods for studying structures of large proteins and protein complexes.
Recently, we have engaged in a project to develop methods for characterizing the health conditions of human individuals from the composition and concentrations of metabolites. Our goal is to develop NMR and mass spectroscopy methods that will allow us to identify individuals with chronic myologenic leukemia (CML) from healthy persons. The methodology being developed has the potential of rapidly monitoring, in a non-invasive way, the status of patients undergoing drug treatment. If successful this approach can be applied for diagnosis and monitoring numerous other diseases.