Structural analysis of a fiber-pseudotyped adenovirus with ocular tropism suggests differential modes of cell receptor interactions

Adenovirus (Ad) entry into cells is initiated by the binding of the fiber k nob to a cell surface receptor. The coxsackie- and adenovirus receptor (CAR ) functions as the attachment receptor for many, but not all, Ad serotypes, Ad type 37 (Ad37), a subgroup D virus that causes keratoconjunctivitis in humans, does not infect cells via CAR despite demonstrated binding of the A d37 knob to CAR. We have pseudotyped a fiber deletion Ad5 vector with the A d37 fiber (Ad37f), and this vector retains the ocular tropism of Ad37, Here we present a cryo-electron microscopy reconstruction of Ad37f that shows t he entire Ad37 fiber, including the shaft and knob domains. We have previou sly proposed that Ad37 may not utilize CAR for cell entry because of the ge ometric constraints imposed by a rigid fiber (E. Wu, J, Fernandez, S, K, Fl eck, D, Von Seggern, S, Huang, and G, R, Nemerow, Virology 279:78-89, 2001) , Consistent with this hypothesis, our structural results show that the Ad3 7 fiber is straight acid rigid, Modeling of the interaction between Ad37f a nd host cell receptors indicates that fiber flexibility or rigidity, as wel l as length, can affect receptor usage and cellular tropism.