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Adenoviruses are common human pathogens causing a number of infectious diseases. They have been found in virtually all organs, producing symptoms ranging from the common cold to pneumonia. Additionally, they also cause a variety of clinical symptoms such as epidemic keratoconjunctivitis, pharyngoconjunctival fever, infantile gastroenteritis, cystitis and urinary tract infections. Individuals with a poorly functioning immune systems are especially prone to severe life-threatening infections. In 1977 Philip Sharp and Richard Roberts discovered the ability of Adenoviruses to split genes, and were in 1993 awarded the Nobel Prize in Physiology and Medicine for their discovery. Today, Adenoviruses are mostly studied for the ability to be used as delivery vehicles in gene therapy. We here studied Adenoviruses binding to the cellular receptor CD46, characterizing the binding mechanism at an atomic level. We used a combination of biological and biochemical methods connecting structure and function to define the Adenovirus interaction with CD46. Our work will have implications for drug design, focusing on reducing Adenovirus complications during organ transplantation.