Biomolecular Sciences Seminar Series

Dr. Tyler Dangerfield, University of Nevada

Title: Molecular Machines in Motion: Using Transient Kinetics to Advance Antiviral and Gene Therapies

Abstract: Understanding the molecular mechanisms governing nucleic acid polymerases and mobile genetic elements is essential for the development of next-generation antiviral therapies and precise gene-delivery technologies. This seminar will explore how transient kinetic analysis and other biochemical techniques allow us to resolve the discrete mechanistic steps underlying viral RNA synthesis and retrotransposon-mediated gene insertion.
First, I will discuss studies on the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). By quantifying the kinetic "decision-making" of the enzyme, we reveal that RdRp is highly processive and unexpectedly incorporates the antiviral drug Remdesivir more efficiently than its natural substrate, ATP. I will share structural and kinetic evidence showing how this incorporation stalls the RdRp complex by blocking RNA translocation, providing a blueprint for the design of more potent nucleotide analogs.
In the second half of the talk, I will present the first comprehensive mechanistic framework for R2 non-long terminal repeat (non-LTR) retrotransposition. Using a combination of kinetic and biochemical approaches, we have defined the pathway from initial target site recognition to final gene integration. These findings not only offer deep mechanistic insights into a promising gene therapy platform but also establish the fundamental weak points for engineering retrotransposon systems capable of safe, site-specific genome insertion.

Host: Dr. Rajesh Nagarajan, Department of Chemistry