Structure, Function and Inhibition of Human ADP-ribosyltransferases

Human ADP-ribosyltransferases (PARPs, TNKSs) catalyze a transfer of ADP-ribose from NAD+ to target proteins. Structures of PARP catalytic domains have been elucidated by protein crystallography facilitating the development of small molecule inhibitors some of which have entered the clinics. We are now reaching towards understanding how the multidomain PARPs function by addressing several key questions in PARPs oligomerization, protein-protein and DNA-protein interactions. The project will address key differences in human PARP enzymes and elucidate the structures of macromolecular complexes at atomic resolution with protein crystallography, cryo-EM and NMR, and complementing this with biochemical methods. We will study structural changes during activation of the catalytic ADP-ribosyltransferase domain upon formation of macromolecular complexes and use a range of biophysical techniques to combine information into a functional models of the enzymes.

PARP and TNKSs complexes control key signalling events of the cell through interactions and posttranslational modifications, which modulate stability of macromolecular assemblies in the cytoplasm and in the nucleus. ADP-ribosylation signaling is often misregulated in diseases like cancer or PARPs promote proliferation and survival of cancer cells. Small molecule inhibitors interfering with the catalytic activity or with protein-protein interactions could provide new tools to and enable development of novel therapies.