Virology Faculty Member - Stephen Harrison

Stephen Harrison

Professor of Biological Chemistry and Molecular Pharmacology

Harvard Medical School
SGMB, Room 130
250 Longwood Avenue
Boston, MA 02115
Tel: 617-432-5609
Fax: 617-432-5600
Email: schadmin@crystal.harvard.edu



We are structural biologists concerned with the organization and dynamics of macromolecular assemblies. We ask the following kinds of questions. (1) What is the molecular structure of viruses and viral proteins and how do their structures relate to their function in the virus particle or in the cell? (2) How do viruses enter cells? (3) Can we ultimately put together a "molecular movie" of viral entry? (4) What is the underlying basis for antibody "affinity maturation" in the immune response to viral infection or vaccination?

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 membrane 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. We have studied the envelope proteins of flaviviruses and of HIV/SIV in some detail, to map out the conformational changes that accompany membrane fusion. We are using this structural information to devise screens for fusion inhibitors and to probe the mechanism of bilayer fusion using single-molecule approaches. Our recent work on non-enveloped viruses focuses on rotaviruses, again with the goal of mapping the conformational changes and bilayer interactions that lead to membrane disruption.

During proliferation of antibody-producing B-cells responding to a viral antigen, somatic hypermutation of the antibody variable regions and selection for cells expressing tightly binding antibodies yields mutated antibodies with substantially higher affinity for antigen than those produced in the initial response. Techniques for cloning the rearranged heavy- and -light chain variable regions from donor samples now allow one to infer intermediates in this affinity maturation and hence to visualize its structural basis. The understanding gained from this approach, which we are applying to the immune response to influenza virus and to HIV, may lead to improved vaccine design strategies.
























Last Update: 10/22/2013



Publications

Modis, Y., Ogata, S., Clements, D. & Harrison, S.C. Structure of the dengue virus envelope glycoprotein after membrane fusion. Nature, 427: 313-319 (2004).

Dormitzer, P., Nason, E.B., Prasad, B.V.V., Harrison, S.C. “Structural rearrangements in the membrane penetration protein of a non-enveloped virus” Nature 430: 1053-1058 (2004).

Harrison, S.C. Viral membrane Fusion. Nature Structural & Molecular Biology 15: 690-698 (2008).

Aoki, S.T., Settembre, E.C., Trask, S.D., Greenberg, H.B., Harrison, S.C., Dormitzer, P.R. Structure of Rotavirus Outer-Layer Protein VP7 Bound with a Neutralizing Fab. Science 324: 1444-1447 (2009).

Chen, J.Z., Settembre, E.C., Aoki, S.T., Zhang, X., Bellamy, A.R., Dormitzer, P.D., Harrison, S.C., Grigorieff, N. Molecular interactions in rotavirus assembly and uncoating seen by high-resolution cryo-EM. PNAS 106: 10644-10648 (2009).

Abraham, J., Corbett, K.D., Farzan, M., Choe, H., Harrison, S.C., Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses. Nature Structural & Molecular Biology 17: 438-444 (2010).

Settembre, E.C., Chen J.Z., Dormitzer, P.D., Grigorieff, N., Harrison S.C. Atomic model of an infectious rotavirus particle. EMBO Journal 30(2): 408-416 (2011).

Whittle, J.R.R., Zhang, R., Khurana, S., King, L.R., Manischewitz, J., Golding, H., Dormitzer, P.D., Haynes, B.F., Walter, E.B., Moody, M.A., Kepler, T.B., Liao, H-X., Harrison, S.C. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. PNAS 108(34): 14216-21 (2011).

Schmidt, A. G., Lee, K., Yang, P. L., Harrison, S. C. Small-molecule inhibitors of dengue-virus entry. PLoS Pathogens 8(4): 1-10 (2012).

Schmidt, A.G., Xu, H., Khan, A.R., O'Donnell, T., Khurana, S., King, L.R., Manischewitz, J., Golding, H., Suphaphiphat, P., Carfi, A., Settembre, E.C., Dormitzer, P.D., Kepler, T.B., Zhang, R., Moody, M.A., Haynes. B.F., Liao, H-X., Shaw, D.E., Harrison, S.C. Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. PNAS 110 (1): 264-269 (2013).

Ivanovic, T., Choi, J.L., Whelan, S.P., van Oijen, A.M., Harrison, S.C. Influenza-virus membrane fusion by cooperative fold-back of stochastically induced hemagglutinin intermediates. eLIFE 1: 1-20 (2013).



© 2013 by the President and Fellows of Harvard College