Stephen C. Harrison
We are structural biologists concerned with the organization and dynamics of macromolecular assemblies. We ask the following kinds of questions. (1) How do viruses assemble and get into and out of cells? (2) What are the molecular mechanisms of vesicular membrane traffic, particularly in the clathrin-coated vesicle pathway? (3) What is the molecular architecture of a kinetochore and how does this architecture embody its required mechanical and signal-transducing properties?
(1) We are particularly interested in determining the molecular events that accompany penetration of a virus into a cell - a process that takes the form of membrane fusion in the case of enveloped viruses and of membane perforation in the case of non-enveloped viruses. Crystallographic and electron microscopic analyses of viruses and viral proteins are at the core of our efforts to understand these steps. In the case of membrane fusion, we are also using the structural information to devise screens for fusion inhibitors and to probe the mechanism of bilayer fusion using single-molecule approaches (this last, in collaboration with Antoine van Oijen in this department). (2) A complete molecular picture of a clathrin coat, put together from cryoEM reconstructions and crystallographic analyses of clathrin fragments and non-clathrin components, has allowed us to design experiments to probe the mechanism of clathrin coat assembly and disassembly. These studies are in conjunction with analyses, using live-cell imaging, of in vivo clathrin-coat dynamics (collaboration with Tomas Kirchhausen, IDI and Dept. of Cell Biology). (3) The kinetochore of budding yeast is an assembly of more than 50 protein species. Together with the laboratory of Peter Sorger (Dept. of Systems' Biology), we have undertaken to build up a three-dimensional picture of a yeast kinetochore, staring with efforts to crystallize some of its constituent protein complexes.
Modis, Y., Ogata, S., Clements, D. & Harrison, S.C. Structure of the dengue virus envelope glycoprotein after membrane fusion. Nature, 427: 313-319 (2004).
Fotin, A., Cheng, Y., Sliz,P., Grigorieff, N., Harrison, S.C., Kirchhausen, Walz, T. “Molecular model for a complete clathrin lattice from electron cryomicroscopy” Nature in 432: 573-579 (2004).
Chen, B., Vogan, E.M., Gong, H., Skehel, J.J., Wiley, D.C., Harrison, S.C. “Structure of an unliganded simian immunodeficiency virus gp120 core” Nature 433: 834-841 (2005).
Frey, G., Rits-Volloch, S., Zhang, X., Schooley, R., Chen, B., Harrison, S.C.. “Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion.” PNAS, 103 (38): 1938-13943 (2006).
Wei, R.R., Al-Bassam, J., Harrison, S.C. “The Ndc80/HEC1 complex is a contact point for kinetochore-microtubule attachment.” Nature Structural & Molecular Biology 14 (1): 54-59 (2007).
Panne, D., Maniatis, T., Harrison, S.C. “An Atomic Model of the Interferon-b Enhanceosome” Cell 129: 1111-1123 (2007).