We explore the relationships between sequence, structure, folding and function in biomolecules. We are particularly interested in poly(ADP-ribose) (PAR) structural biology. PAR is a biochemical signal that controls important processes in cells. It is involved in DNA damage repair, chromatin remodeling, the cell cycle, stress responses, antiviral processes, and many other signaling pathways.
Solution NMR spectroscopy and other biochemical, biophysical and computational approaches are applied to understand protein families that recognize PAR. Understanding structural and dynamical variations allows us to develop theories of molecular recognition. PARylation pathways are targets for drug discovery due to their involvement in cancer, the immune system, and neurological disease. Hence, this reseaerch should also allow the discovery of new classes of PARP inhibitors.
PAR is mainly found as a post-translational modification of proteins. It is synthesized by PAR polymerases (PARPs). These enzymes transfer one or more ADP-ribosyl units to acceptor residues on proteins to form PAR. While we know the basic steps of this reaction, many aspects of PARP biochemistry remain unclear. For example, PARPs contain accessory domains that are probably involved in regulating enzyme activity or mediating intermolecular interactions. Understanding the functions of these modules is central to working out the roles of these proteins and their products in biology.
Nucleic acid-binding proteins
Nucleic acid-binding proteins are essential in all domains of life. In eukaryotic cells, they function in crucial processes such as transcription and translation. In viruses, they replicate and package the genome and interact with host cell molecules. Cells have evolved pathways to recognize the presence of viruses, while viruses have adopted strategies to combat host cell defenses, such as interfering with the expression of antiviral genes. Nucleic acid recognition is often central to these mechanisms.
We study the structural biology of nucleic acid recognition and structure-function relationships in nucleic acid-binding protein families. Viral and eukaryotic systems are both of interest. Viruses are a prolific source of novel protein folds, and characterizing their proteins provides valuable new information about emerging pathogens that can be used to clarify evolutionary relationships and develop new antiviral drugs.
Publications in Pubmed