Abstract

The influenza virus haemagglutinin (HA) glycoprotein is being studied as a prototype membrane surface antigen. X-ray crystallographic, Electron microscopic, and biochemical studies are proposed to investigate the functions of this protein on the viral membrane surface, and to learn how those functions contribute to recurrent epidemics in man. How the virus binds to a target cell is being studied by X-ray structural studies of wild type and mutant HAs with altered receptor specificities, complexed with receptor analogs and receptor fragments. The mechanism of membrane fusion mediated by the HA to effect viral penetration into a host cell is being studied by X-ray studies of a fusion inactive precursor HAO, by crystallization studies of protein-detergent complexes and EM image analysis of the hydrophobic, fusion-active HA conformation, and by calculations and modifications on mutant HAs. The interaction of the HA with molecules of the human immune system is being studied by structural studies of antigenic variants, both monoclonal antibody selected and natural. This includes the production of novel antigenic types by molecular cloning. Attempts will be made to crystallize an antibody-antigen complex suitable for X-ray analysis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI013654-09
Application #
3125520
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1977-01-01
Project End
1989-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
9
Fiscal Year
1985
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

  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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