Viruses are among the best-known and studied pathogens and infect virtually every living organism from bacteria to man. As viruses are parasites of their hosts, the life cycle of any virus is inextricably tied to that of the host cell. Despite this dependence, all viruses share a number of essential tasks, which they must accomplish for survival. A virus must find and recognize a cell in which it can replicate, release its genome into the cell, generate new viral components and assemble these components into precursors that mature into a stable progeny virion which is released from the host cell and transmitted to encounter a new host. Viruses accomplish these tasks in different ways as a result of adaptation to different cellular environments. Each task involves interactions between components within the context of the whole virion and hence requires the visualization of the entire structure at which the techniques of cryo-transmission electron microscopy (cryoTEM) and three-dimensional (3D) image reconstruction ('cryo-reconstruction') excel. We will exploit these techniques to study a diverse range of viruses, including those that infect humans and other mammals, insects, bacteria, and algae. Numerous projects funded by the current grant have illustrated the structural response of different viruses to the common tasks of the viral life cycle. This proposal involves continued as well as new studies that focus on structural investigations of viruses and virus complexes and dynamic events that lie beyond the current realm of crystallographic technology. The large number and extent of our studies are made possible through several fruitful collaborations, which provide important correlative information from biochemical, genetic, and X-ray crystallographic experiments. Our analyses often gain important insights by combining cryo-reconstruction data with available atomic models. Modeling experiments, for example, can provide 'pseudo-atomic' resolution details about the orientation and binding sites of antibody and receptor molecules on viral capsid surfaces that can be tested and refined by means of targeted molecular genetics experiments. Icosahedral as well as non-icosahedral viruses will be studied. These include representatives of several different virus families, all of which are excellent model systems for studying form and function: Myoviridae, Reoviridae, Parvoviridae, Picornaviridae, Podoviridae, Phycodnaviridae, and Iridoviridae.
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