Abstract

The influenza virus haemagglutinin (HA) glycoprotein is being studied both as a prototype membrane surface molecule and as a functional component of a viral envelope. X-ray crystallographic studies of the HA from the human, 1968 Hong Kong virus strain produced atomic models from which chemically detailed conclusions about virus functions can be deduced. The detail of these models also permits the design of biochemical, recombinant DNA, and cell biological experiments on the mechanisms of the viral activities. A long-term goal is to develop strategies to intervene in the viral processes to prevent infection. How the virus binds to cells is being studied by X-ray structural analysis of complexes between the HA and synthetic receptor analogs and with complexes between sialocides and affinity mutants of the HA. The structure of the HA from an animal influenza virus Duck/Ukraine/63 the progenitor of the 1968 human Hong Kong strain will be determined. The energetics of the receptor binding interactions are being measured in parallel with X-ray experiments by NMR. Recombinant DNA methods are being used to create site-directed mutations in the interacting residues and to provide quantities of novel molecular species for NMR and X- ray studies. The mechanism of membrane-fusion by which many enveloped animal virus enter cells is being studied by structural analysis of a fusion active and precursor, inactive form of the HA. The structure of membrane fusion mutants and a second fusion active glycoprotein from Influenza C virus are also being studied.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI013654-15
Application #
3125527
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1977-01-01
Project End
1994-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
15
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Harvard University
Department
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

Russell, R J; Gamblin, S J; Haire, L F et al. (2004) H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes. Virology 325:287-96
Gamblin, S J; Haire, L F; Russell, R J et al. (2004) The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303:1838-42
Swalley, Susanne E; Baker, Brian M; Calder, Lesley J et al. (2004) Full-length influenza hemagglutinin HA2 refolds into the trimeric low-pH-induced conformation. Biochemistry 43:5902-11
Ha, Ya; Stevens, David J; Skehel, John J et al. (2003) X-ray structure of the hemagglutinin of a potential H3 avian progenitor of the 1968 Hong Kong pandemic influenza virus. Virology 309:209-18
Ha, Ya; Stevens, David J; Skehel, John J et al. (2002) H5 avian and H9 swine influenza virus haemagglutinin structures: possible origin of influenza subtypes. EMBO J 21:865-75
Ha, Y; Stevens, D J; Skehel, J J et al. (2001) X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs. Proc Natl Acad Sci U S A 98:11181-6
Chen, J; Skehel, J J; Wiley, D C (1998) A polar octapeptide fused to the N-terminal fusion peptide solubilizes the influenza virus HA2 subunit ectodomain. Biochemistry 37:13643-9
Martin, J; Wharton, S A; Lin, Y P et al. (1998) Studies of the binding properties of influenza hemagglutinin receptor-site mutants. Virology 241:101-11
Weissenhorn, W; Calder, L J; Wharton, S A et al. (1998) The central structural feature of the membrane fusion protein subunit from the Ebola virus glycoprotein is a long triple-stranded coiled coil. Proc Natl Acad Sci U S A 95:6032-6
Weissenhorn, W; Carfi, A; Lee, K H et al. (1998) Crystal structure of the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain. Mol Cell 2:605-16

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