Our research program currently has three major areas of focus: 1) structure and function of viruses and viral proteins, 2) development of tools for structure-based drug design, and 3) structural studies of proteins involved in nuclear transport.
Our studies of virus structure and function began with the characterization of the structure of poliovirus and several related small icosahedral RNA viruses. Although these viruses are relatively simple and arguably the best understood viral pathogens, they must perform a variety of biological functions at various stages of their life-cycle, many of which remain poorly characterized. Current studies of these viruses are focused on two major questions: 1) structural and biochemical dissection of the cell entry pathway (including structural studies of the receptor, virus-receptor complex, and several cell entry intermediates) and 2) structural characterization of RNA-protein interactions that regulate translation and replication of the viral genome.
In collaboration with Don Coen we have initiated a program of structural studies of essential proteins from herpes viruses. Our initial focus has been on the interaction between the DNA polymerase of HSV1 and an accessory protein, UL42, which is required for processive DNA synthesis. We have recently solved the structure of a complex between UL42 and the minimal C-terminal domain of the polymerase. We have also initiated a program of study of protein-protein and protein-RNA interactions in hepatitis delta virus. We have solved the structure of the oligomerization domain of the hepatitis delta antigen, and are now working on expressing other forms of the protein including the RNA binding domain and the full-length protein. The oligomerization domain of the receptor forms an unusual square-planar octamer in which each side of the square is made up of an antiparallel coiled-coil. We are currently investigating the possibility of using the octamer as a platform for high valency display of protein domains.
Our interest in virus structures has naturally led us to investigate methods for using the structures to design antiviral. We are currently developing methods in which the structures are used to develop templates for structurally-biased combinatorial libraries, and the libraries are screen for ligands with antiviral activity.
Finally, we have begun a collaboration with Pam Silver to develop a program of structural studies of proteins involved in nuclear transport. Our initial focus has been on an arginine methyltransferase, HMT1, that plays a role in export of messenger RNAsfrom the nucleus.
Selected Publications:
Wien, M.W., M. Chow, J.M. Hogle (1996). Poliovirus: new insights
from an old paradigm. Structure 4:763-767.
Wien, M.W., Curry, S., Filman, D.J., J.M Hogle (1997). Structural studies of poliovirus mutants that overcome receptor defects. Nature Structural Biology 8:666-679.
Zuccola, H.J., Rozelle, J.E., Lemon, S.M., Erickson, B.W.,
and J.M. Hogle (1998). Structural basis of the oligomerization of
hepatitis delta antigen. Structure 6:821-830.