The aim of this project is to determine the 3-dimensional stucture of neuraminidase (NA) molecules from different subtypes of type A influenza virus and of neuraminidase molecules from antigenic variants within one subtype. This information should lead to a precise definition of the structure of the active centre of the enzyme and the structure of at least some of the antigenic sites. The three dimensional structures of two N2 neuraminidases at 2.9 angstrom resolution are in hand and separate crystallographic refinement of these structures will be undertaken to enable a first description of the stereochemical basis of antigenic drift in influenza. 3 angstrom diffraction data have also been collected for a monoclonal variant of an N2 neuraminidase. The structure of subtype N9 neuraminidase will be determined using X-ray diffraction data already collected at 1.9 angstrom resolution from crystalline protein. The project is directed toward the development of an effective means to control influenza and the information obtained will: 1. provide knowledge of the precise molecular changes which occur during antigenic drift in influenza virus. 2. provide accurate information about the active site of neuraminidase which may lead to the fabrication of molecules which will specifically interact with the enzyme active centre of the neuraminidase and stop the spread of the virus in the body. This project requires high resolution X-ray diffraction data from influenza neuraminidase. Since much of the data is already in hand in our laboratory we know of no U.S. laboratory prepared to commit itself to such a study at the present time.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI021659-01
Application #
3131882
Study Section
Biophysics and Biophysical Chemistry B Study Section (BBCB)
Project Start
1985-01-01
Project End
1988-07-31
Budget Start
1985-01-01
Budget End
1986-07-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Commonwealth Sci & Ind Research Org
Department
Type
DUNS #
City
Parkville
State
Country
Australia
Zip Code
Tulip, W R; Varghese, J N; Webster, R G et al. (1992) Crystal structures of two mutant neuraminidase-antibody complexes with amino acid substitutions in the interface. J Mol Biol 227:149-59
Tulip, W R; Varghese, J N; Laver, W G et al. (1992) Refined crystal structure of the influenza virus N9 neuraminidase-NC41 Fab complex. J Mol Biol 227:122-48
Tulip, W R; Varghese, J N; Baker, A T et al. (1991) Refined atomic structures of N9 subtype influenza virus neuraminidase and escape mutants. J Mol Biol 221:487-97
Tulip, W R; Varghese, J N; Webster, R G et al. (1989) Crystal structures of neuraminidase-antibody complexes. Cold Spring Harb Symp Quant Biol 54 Pt 1:257-63
Varghese, J N; Webster, R G; Laver, W G et al. (1988) Structure of an escape mutant of glycoprotein N2 neuraminidase of influenza virus A/Tokyo/3/67 at 3 A. J Mol Biol 200:201-3
Laver, W G; Webster, R G; Colman, P M (1987) Crystals of antibodies complexed with influenza virus neuraminidase show isosteric binding of antibody to wild-type and variant antigens. Virology 156:181-4
Baker, A T; Varghese, J N; Laver, W G et al. (1987) Three-dimensional structure of neuraminidase of subtype N9 from an avian influenza virus. Proteins 2:111-7
Air, G M; Webster, R G; Colman, P M et al. (1987) Distribution of sequence differences in influenza N9 neuraminidase of tern and whale viruses and crystallization of the whale neuraminidase complexed with antibodies. Virology 160:346-54
Tulloch, P A; Colman, P M; Davis, P C et al. (1986) Electron and X-ray diffraction studies of influenza neuraminidase complexed with monoclonal antibodies. J Mol Biol 190:215-25
Air, G M; Laver, W G (1986) The molecular basis of antigenic variation in influenza virus. Adv Virus Res 31:53-102