Our research group is interested in the molecular mechanism that underlies the signaling of protein tyrosine kinases and ubiquitin ligases. Protein kinases are well established drug targets in oncology and inflammatory diseases. Kinases can access multiple well defined structural states and we are studying how small molecule inhibitors interact with these structures.

The aim for this NIH funded project is to understand the conformational exchange between kinase conformations as well as to understand the inhibitory mechanism of kinase inhibitors. For this we are using X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR), protein engineering and other biophysical methods in collaboration with computational biologists. The ubiquitin system relies on a highly modular system of enzymes to ligate ubiquitin onto substrate proteins which in many cases leads to the degradation of the substrate protein via the proteasome. The potential of the ubiquitin system as a therapeutic target is illustrated by the success of the proteasome inhibitor bortezomib in the treatment of multiple myeloma. We are interested in applying concepts from the field of protein kinase research to the study of ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3) with the aim of enabling specific therapeutics. Our current aim is to study the change in substrate spectra of ubiquitin ligases upon aging in yeast cells. This is work is generously supported by the Ellison Medical Foundation.