"How Nature Achieves Remarkable Enzymatic Specificity: Dissecting Taq DNA Polymerase and Botox Protease"

Prof. Gregory A. Weiss

Departments of Chemistry, Pharmaceutical Sciences, and Molecular Biology & Biochemistry

University of California, Irvine 

Host: Brett VanVeller

Abstract: This talk will describe dissecting and enhancing the function of ultra-specific enzymes – Taq DNA polymerase and the protease used in Botox. Both enzymes manage remarkable feats of substrate specificity with Taq incorporating one incorrect base every 5,000 or more bases and Botox protease cleaving only a single amide bond out of millions in the human proteome. With collaborator Prof. Phil Collins (UCI), we have spot-welded individual proteins into nanometer-scale electronic circuits, termed “nanophones,” to record the sounds made by proteins in motion. The tethered single molecule can be examined at high-speeds (microsecond resolution) for long durations (up to weeks) in real-time during enzymatic catalysis. The approach has been used to dissect the inner workings of several enzymes, including DNA polymerases and protein kinase A. Recently, we have used these nanocircuits to examine the PCR enzyme, Taq DNA polymerase. This enzyme functions at elevated temperatures with fast conformational dynamics, which challenge conventional single molecule studies. Taq’s temperature sensitivity results from faster speed during its rate-determining substrate binding step.  We next turned attention to a champion of specific enzymes, Botox protease (Botulinum neurotoxin serotype A, BoNT/A). Fifteen rounds of directed evolution uncovered insights into its specificity and yielded a new potential therapeutic. In short, both Taq and BoNT/A protease achieve their vaunted catalytic specificity through precatalytic binding steps to test substrate identity. 

Bio: Gregory Weiss earned his PhD from Harvard in 1997 for research in the laboratory of Prof. Stuart L. Schreiber focused on non-peptide ligands to MHC receptors. He next pursued post-doctoral studies with Dr. Jim Wells, then at Genentech.  In 2000, he joined the faculty at UCI where his laboratory focuses on the interface between chemistry and biology, including bioconjugation, bioelectronics, and the dissection, and engineering of enzymes.  Tenured in 2006, he is a full Professor. His awards include Outstanding Professor in the School of Physical Sciences at UCI (elected by the graduating students), Beckman Foundation Young Investigator, and Fellow of the American Association for the Advancement of Science.  He was awarded an Ig Nobel Prize in Chemistry for leading the team that "partially unboiled the egg."  The Co-Founder of three biotech companies, Greg was named UCI’s Entrepreneurial Leader of the Year in 2018 and a Faculty Innovation Fellow in 2020.  In January 2026, he will move to NYU and become their Chair of the Department of Chemistry.