Stephen C. Harrison, Ph.D.

Professor of Biological Chemistry and Molecular Pharmacology

Howard Hughes Medical Institute
Laboratory of Molecular Medicine
Enders Research Building
Children's Hospital
320 Longwood Avenue
Boston, MA 02115
tel: (617) 355-7372
fax:(617) 355-3506
email:schenders@crystal.harvard.edu
13 postdoctoral fellows, 2 graduate students

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 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 particular detail, to map out the conformational changes that accompany membrane fusion.  The HIV and SIV projects are in collaboration with Bing Chen (Children’s Hospital).  We are using this structural information to devise screens for fusion inhibitors and to probe the mechanism of bilayer fusion using single-molecule approaches, the latter in collaboration with Antoine van Oijen (BCMP).  Our work on non-enveloped viruses focuses on reo- and rotaviruses, again with the goal of mapping the conformational changes and bilayer interactions that lead to membrane disruption. 

References:

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).

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).

Heldwein, E.E.,  Huan, L., .Bender, F.C., Cohen,  G.H., Eisenberg, R.J., Harrison, S.C. “Crystal structure of glycoprotein B from Herpes Simplex Virus 1”  Science 313:  217-220. (2006)

Zhang, L., Chandran, K., Nibert, M.L., Harrison, S.C. “Reovirus µ1 Structural Rearrangements That Mediate Membrane Penetration” J. Virol 80:  12367-76 (2006).