Structural Biology of Signaling domains
Lynparza (Olaparib), a drug for treatment of a certain type of ovarian cancer, is an inhibitor of PARP1 and related enzymes. PARP enzymes are ADP-ribosyltransferases: They catalyze ADP-ribosylation, a common post-translational modification (PTM) of proteins in the nucleus, in the cytosol, and on the cell surface.
ADP-ribosylation contributes to the control of gene transcription, DNA repair, and a variety of other biological processes.The ADP-ribose transferases fall into two functional subfamilies; mARTs mono-ADP-ribosylate their targets, whereas PARPs transfer units onto growing chains of ADP-ribose on their tagets. The most widely known of these transferases is PARP1 (ARTD1), a target for cancer and ischemia drug development.
There is a wide range of potential therapeutic applications for inhibitors of the enzymes and of the proteins that recognize this PTM. Before these classes of compounds can live up to their full potential, we need to understand the molecular mechanisms of their actions:
- How do PARP inhibitors kill cancer cells?
- Which PARP enzymes should we inhibit for the best therapeutic outcome in a certain type of disease?
- Can we develop selective PARP inhibitors?
- Can we target the binder domains with small compound inhibitors?
- Can we exploit inhibitors of bacterial ADP-ribosylating toxins for development of anti-infective therapies?