The SARS CoV 2 Macrodomain and how to inhibit it
The nonstructural protein 3 (NSP3) macrodomain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Mac1) removes adenosine diphosphate (ADP) ribosylation posttranslational modifications, playing a key role in the immune evasion capabilities of the virus responsible for the coronavirus pandemic. Starting from a collaborative X-ray-based fragment screen, multiple computational strategies and structure-based design has facilitated the development of potent inhibitors.
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James Fraser, Ph.D.
James was an undergraduate at McGill University, where he worked in the lab of Dr. Francois Fagotto on Xenopus developmental biology. During the summers, he returned to his hometown of Toronto and worked in Dr. Alan Davidson’s lab on TetR repressor biophysics and bacteriophage genomics.
He moved to California in 2005 to do his Ph.D. in Molecular and Cellular Biology at UC Berkeley. There, he worked with Dr. Tom Alber creating biophysical methods to characterize protein side chain flexibility in high resolution X-ray electron density maps. They applied these techniques to study connections between conformational dynamics and enzymatic catalysis, showing that room temperature, but not standard cryogenic, X-ray data collection could reveal the structural basis for critical functional motions.
Near the end of his Ph.D., he was an EMBO Short-Term Fellow in Dr. Dan Tawfik’s lab at the Weizmann Institute of Science. Concurrently, he authored the problems and solutions manual for the physical chemistry textbook The Molecules of Life by Kuriyan, Konforti, and Wemmer.
In January 2011, James started his independent career as a QB3 at UCSF Fellow affiliated with the Department of Cellular and Molecular Pharmacology. In January 2013, he was appointed as an Assistant Professor in the Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences (QB3) with promotion to Associate Professor in 2016, and Full Professor in 2020. From 2022-2023, he was Vice Dean of Research for the UCSF School of Pharmacy. Since August 2023, he has been the Ernest L. Prien Professor and Chair of the Department of Bioengineering and Therapeutic Sciences.
The lab is also part of the Macromolecular Structure Group at UCSF and BioXFEL, a Science and Technology Center established by the National Science Foundation. We maintain a deep connection with Macomolecular Crystallography Beamline 8.3.1., directed by Dr. James Holton, at the Advanced Light Source. James is also a Faculty Scientist in the Molecular Biophysics and Integrated Bioimaging Division of Lawrence Berkeley National Lab, and Associate Director of the Quantitative Biosciences Initiative.
In addition to all the exciting developments in the lab, James has long standing interests in teaching, baseball statistics, and juggling. James was also on the board of ASAPbio, a non-profit organization dedicated to accelerating the pace of scientific discovery by making research outputs more accessible and reusable. The lab is committed to publishing our code, disseminating our datasets, posting manuscripts on preprint servers, and participating in open peer review. He is the co-creator of UCSF Talks, an aggregator of all the discovery science seminars at UCSF.
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