ESR11 – Structural Analysis of Adenovirus Binding to Integrins
Faculty of Science and Faculty of Medicine, University of Tübingen (Germany)
Viruses use highly specific recognition processes to engage the target cell. The initial interaction between a viral capsid protein and the cell determines cell and host tropism as well as pathogenicity of a virus, and it often triggers and enables subsequent interactions that then allow the virus to enter the cell. Adenoviruses are established human pathogens that can cause a variety of serious diseases and are also of interest for gene delivery purposes as they are able to easily package and deliver foreign genomes to a target cell. While the structural basis of adenovirus binding to its protein receptors CAR and CD46 has been established, much less is known about the interactions of some of these virus strains with glycan receptors. In addition, all adenoviruses use integrin receptors for entry, and the structural basis of this interaction is entirely unknown. It is clear, however, that understanding the rules that allow adenoviruses to engage these attachment and entry receptors will greatly facilitate the use of these particles for targeting specific cell types, such as certain tumor cells that for example express high levels of specific glycan receptors. The predominant aim of this PhD project is to investigate structural aspects of the interactions of adenoviruses with both glycan and integrin receptors. To achieve this, the relevant recombinantly expressed virus proteins (fiber, penton) will be complexed with their respective receptors and the structures will be solved by X-ray crystallography in combination with additional biophysical approaches that can serve to support the observed interactions. The interactions will also be probed with site-directed mutagenesis to validate the observed contacts.