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The overall objective of our research is to understand subcellular structure and the control of macromolecular assembly. We use direct structural approaches -- in particular, X-ray crystallography. Our present work tackles three broad questions about molecular localization in cells: (1) How do viruses assemble and get into and out of cells? (2) How do proteins that control transcription recognize, both individually and in combination, their DNA binding sites? and (3) How does the regulated assembly and dissociation of protein complexes mediate intracellular signaling?
(1) Crystallographic studies of viruses and viral proteins reveal details of their molecular architecture. Viruses interact with cell surface receptors and find their way into the cytoplasm of the nucleus. Our analysis of the structural basis for such recognition and localization events uses the virus structures as starting points. (2) The recognition by proteins of specific DNA sequences is a fundamental event in the control of gene expression. We study this recognition by examining crystals of complexes between such regulatory proteins and the DNA sites to which they bind. (3) Specific protein associations occur in response to defined events at the cell surface. For example, tyrosine kinases participate in many signal transduction pathways by generating phosphorylated sites for binding of other proteins. Crystallographic studies of such interactions reveal the basis for specificity and provide a context for thinking about drug design.
Selected Publications:
Müller, C.W., Rey, F.A., Sodeoka, M., Verdine, G.L., & Harrison, S.C. (1995). Structure of the NF-kB p50 homodimer bound to DNA. Nature 373: 311-317.
Rey, F.A., Heinz, F. X., Mandl, C., Kunz, C. & Harrison, Stephen C. (1995). The envelope glycoprotein from tick-borne encephalitis virus at 2 Å resolution. Nature 375:291-298 (1995).
Xu, W., Harrison, S.C. & Eck, M.J. (1997). Three-dimensional structure of human c-Src. Nature 385:595-602.