Description:

The Department of Biochemistry and Molecular Genetics invites faculty, staff, and students to a guest speaker presentation entitled Biochemistry and Pharmacology of the Ubiquitin System, featuring Alexander V. Statsyuk, PhD, Assistant Professor of Chemistry at Northwestern University. 

Tuesday, September 8th, 2015, 10:00 - 11:00 a.m.
Morton 7-660

Presentation Abstract:

Our research program is focused on the development of chemical tools to study the role of ubiquitin signaling. Specifically we have developed small molecule inhibitors of the ubiquitin activating E1 enzyme, which leads to a complete inhibition of the ubiqutin conjugation. E1 enzyme inhibitors inhibit protein degradation, similar to the proteasome inhibitor MG132. However, E1 enzyme inhibitor treatment does not lead to the formation of cytoprotective aggresomes, which limit clinical efficacy of anticancer drug bortezomib.

During these studies we have uncovered the potential of N-acylsulfamates as useful pH-cleavable linkers for a variety of applications. We used these to design a novel class of pH-cleavable photocrosslinkers, which can be generally used to map protein-protein interaction interfaces in vitro. In this method photocrosslinker can be installed anywhere on the protein surface, followed by photocrosslinking with the partner protein, and photocrosslinked sites are identified. Using these reagents we discovered catalytically important residues in E6-AP ligase.

Our other research directions included the development of irreversible tethering technology, a useful technology to discover covalent enzyme and protein-protein interaction inhibitors. Using this technology we discovered first-in-class covalent inhibitors of HECT E3 Nedd4-1 enzyme. Unexpectedly, the discovered inhibitors inhibited Nedd4-1 enzyme processivity (i.e. the ability to elongate polyubiquitin chains). To visualize the binding mode of these inhibitors, we obtained the first crystal structure of Nedd4-1 enzyme bound to its covalent small molecule inhibitor, and subsequently developed more potent inhibitors of Nedd4-1 enzyme. These types of inhibitors are novel and offer opportunities to explore physiological functions of HECT E3 ligase Nedd4-1. Nedd4-1 is an enzyme which is required for viral budding of Ebola virus, degrades α-synuclein, and is required for IGF-1 receptor driven cell growth pathways. Therefore our findings pave the road toward treating viral infections, neurodegenerative diseases, and cancers.

Finally, we will discuss the development of novel fluorescent assays to screen for inhibitors or activators of HECT E3 ubiquitin ligases. Typical assays for E3 ligases are very complex and require 8 reagents. We have developed a novel assay, which only requires 2 reagents, and allows monitoring protein ubiquitination in real time. Finally we will discuss future directions.

Please e-mail Carson Nestler at carson.nestler@northwestern.edu if you have any questions.