03/12/18 -4:00 PM to 5:00 PM
Special Seminar: Professor Justin M. Holub
"Re-imagining Nature’s Scaffold: Designing Synthetic Proteins to Target Biomolecular Interactions"
Biomolecular recognition is an important physiological process by which biomolecules bind and interact with their molecular targets. From a drug design standpoint, such interactions may be exploited in the development of curative agents that target therapeutically-relevant biomolecular interactions or as chemical genetics tools to study the nature of biomolecular recognition on a molecular level. The first half of this seminar will focus on a recent study where we developed a series of synthetic proteins based on scyllatoxin (ScTx) designed to mimic the helical BH3 interaction domain of the pro-apoptotic Bcl-2 protein Bax. ScTx is a small, 31-amino acid protein that folds into an α/β structural motif stabilized by three disulfide linkages. By modifying the number and position of disulfide linkages within our ScTx-Bax mimetics, we were able to identify discrete structural elements within the helical BH3 domain that regulate induced-fit binding interactions with anti-apoptotic Bcl-2 proteins. This study underscores the importance of structural dynamics in facilitating favorable BH3:Bcl-2 interactions and validates ScTx-based ligands as potential modulators of Bcl-2 function. The second half of this lecture will center on the design and synthesis of a novel peptide-based kinase inhibitor that selectively targets MARK2, a protein kinase that phosphorylates the microtubule-associated protein tau. Hyper-phosphorylated tau isoforms have been implicated in neurodegenerative disorders including Alzheimer’s disease and there is considerable interest in developing inhibitors of dysregulated kinase activity in neurons. We have designed a synthetic peptide based on the tau R1 microtubule-binding domain (tR1) that selectively inhibits the MARK2-mediated phosphorylation of tau in vitro and in cultured neurons. These results establish tR1 as a selective kinase inhibitor with significant therapeutic potential and as a tool that may be used to dissect the complex nature of MARK:tau interactions.
Research in Professor Holub's laboratory focuses on the development of chemical tools to investigate biological processes. Researchers use multidisciplinary approaches to design and synthesize non-natural molecules, such as synthetic biologics and profluorescent ligands, to study and manipulate protein-protein interactions. There are currently two main areas of active research: targeting Bcl-2 family proteins with synthetic biologics and monitoring steroid hormone receptor dimerization kinetics using profluorescent ligands.
Professor Holub earned his bachelor's degree from Rider University in Lawrenceville, NJ, and his doctorate from New York University, under the tutelage of Professor Kent Kirshenbaum. He was a post-doctoral research associate at Yale University, working with Professor Alanna Schepartz. He became an assistant professor in the Department of Chemistry and Biochemistry at Ohio University in 2013.