Structural biology of DNA-packaging machines from dsDNA viruses

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Viruses are the most common biological entities on our planet, infecting all living things. In humans, viral infections like herpes and poliovirus cause serious illnesses but, because they are impossible to eradicate using current treatments, they can also persist indefinitely. This persistence often leads to serious health complications, including cancer.Viruses can only replicate inside host cells. During infection, the virus uses specialized molecular machines to copy its genes and to load them into protective capsules, which then spread to other cells. This project will employ cryo-Electron Microscopy and X-ray crystallography to image the machines and watch them in action.Specific Aims:1) Produce virus particles or stable molecular assemblies of individual proteins and nucleic acids2) Determine structures by either X-ray crystallography or cryo-electron microscopy3) Analyse structures and probe biological mechanisms by site-directed mutagenesisNovelty:Understanding how large protein-nucleic acid machines function requires structural knowledge about individual components and complete macromolecular assemblies. Recent advances in cryo-EM approaches allow high resolution structural information to be obtained for complete, multiple component nucleic acid machines. Such structures could be complemented by X-ray structures of individual protein components determined at higher resolution. The project will target molecular motors, for which no structural information is currently available.