Special Seminar - Biochemistry Division
Seminar title: "Structure and dynamics of proteins in DNA and RNA metabolism"
Abstract:
My presentation focuses on our studies of proteins engaged in DNA and RNA transactions. High
fidelity replication of eukaryotic genomic DNA is essential for maintaining chromosomal stability
and for suppressing carcinogenesis. A pivotal player is DNA polymerase d (Pold), which catalyzes
DNA synthesis. Mutations in Pold have been associated with cancer and the etiology of other
diseases. Despite the critical roles of Pold, the mechanism of assembly and regulation remains
unclear. This is in part due to the lack of any structural information on the holoenzyme. We have
determined the near atomic resolution (3.2 Å) cryo-EM structure of yeast Polδ holoenzyme in
the act of DNA synthesis. Using the structure, we are able to address longstanding questions
about both the architecture and its internal dynamics. We uncover the basis of cancer and other
disease mutations and show how the “observed” dynamics is in correspondence with the
“predicted” motion determined via normal mode analysis. Collectively, the structure provides a
framework for understanding DNA transactions at the replication fork.
In the second part of my talk, I will touch upon our early work on developing small molecule
probes targeting essential enzymes from the Zika virus. Since these Zika enzymes have structural
similarities with other faviviral homologs, such as those from Dengue and Yellow Fever viruses,
inhibitors of these enzymes may have broad-spectrum activity. We present our strategy and
discuss challenges associated with viral drug discovery.
