We propose to continue our high resolution crystallographic studies of poliovirus. Poliovirus has become the prototype of an entire family of viruses, the Picornaviridae, which also includes the coxsackieviruses, the rhinoviruses, foot and mouth disease virus, and hepatitis A virus. The importance of these viruses as pathogens has made the entire family, and especially poliovirus, among the best characterized viral pathogens. Structural studies of poliovirus thus provide an excellent opportunity for studying the relationship between viral structure and several important biological properties including viral assembly, recognition and neutralization by the immune system, recognition of specific receptors on susceptible cells, and pathogenesis. We have recently solved the structure of the Mahoney strain of type 1 poliovirus at 2.9 angstrom unit(s) resolution using x-ray crystallographic methods. The model provides, for the first time, a detailed view of the architecture of the poliovirion. The structure has also allowed the three dimensional mapping of the antigenic sites of the virion and provides significant insight into the role of post-translational proteolysis in the assembly of the virus. We propose to extend the structure determination to higher resolution (the crystals diffract to at least 2.2 angstrom unit(s)), to refine the model versus stereochemical and crystallographic constraints, and to continue to use the model to investigate the relationship between the structure and the biological properties of poliovirus. In addition we propose to extend the structural studies to other strains of poliovirus (the Sabin (attenuated) strains of type 1 and type 3 poliovirus and the Lansing stain of type 2 poliovirus) and to several virus related particles (pentamers, empty capsids, cell released virions, and complexes of virus with anti-viral drugs such as arildone). Structural studies of the additional strains will provide insight into the structural basis for serotype differences, phenotypic differences (e.g. temperature sensitivity in the Sabin strains), and particularly in the case of the mouse adapted Lansing 2 the structural basis for receptor recognition and neurovirulence. Structural studies of the virus related particles will provide insight into the structural changes (covalent modifications and quaternary structure changes) which the virus undergoes during its life cycle.
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