Event

Inquires please contact Camille Pride at campride@sas.upenn.edu

Title: Chemistry, Biochemistry, and Pharmacology of the Ubiquitin System

Abstract: Our research program aims to provide critical insights onto physiological functions of the ubiquitin system; one of the most complex and enigmatic systems known to date.

As of today we know that approximately 800 enzymes regulate the dynamic ubiquitination of 19,000 protein substrates thus representing a vast and unexplored area of the human druggable genome.

Over the past five years we have pursued numerous research directions in the ubiquitin system that yielded many useful outcomes.

For example in vitro protein ubiquitination requires at least ATP, E1, E2, and E3 enzymes. We asked whether it is possible to achieve protein ubiquitination with just ubiquitin and E3 ligase, and in the absence of ATP, E1, and E2 enzymes? The answer to this question has led to the useful assay that provides new insights on the biochemistry of E3 ligases, and has led to new drug-discovery assays that can be used to discover new treatments for Ewing's sarcoma and Parkinson's disease. In yet another research project we developed a novel fragment-based drug discovery technique "Covalent tethering" which could be used to discover covalent drug leads for many drug targets that contain cysteines such as E3s and DUBs. Libraries of electrophilic fragments that we designed were requested and used by 10 research groups. Using this technique we discovered a covalent inhibitor of Nedd4-1 ubiquitin ligase with the very unusual mechanism of action. Identified inhibitor switches Nedd4-1 enzyme from processive to the distributive mechanism of polyubiquitin chain synthesis, which is unprecedented. Special assays needed to be implemented to visualize the inhibitory effect of this inhibitor. These findings represent important case studies in E3 ligase inhibitor design, suggesting that inhibitors of similar type can exist for DUBs. Finally, we will highlight our future directions.