Structure of adenovirus complexed with its internalization receptor, αvβ5 integrin

The three-dimensional structure of soluble recombinant integrin alpha(v)beta 5 bound to human adenovirus types 2 and 12 (Ad2 and -12) has been determined at similar to 21-Angstrom resolution by cryoelectron microscopy (cryo-EM). The alpha(v)beta 5 integrin is known to promote Ad cell entry. Cryo-EM has shown that the integrin-binding RGD (Arg-Gly-Asp) protrusion of the Ad2 penton base protein is highly mobile (P. L. Stewart, C. Y. Chiu, S. Huang, T. Muir, Y. Zhao, B. Chait, P. Mathias, and G. R. Nemerow, EMBO J. 16:1189-1198, 1997). Sequence analysis indicated that the Ad12 RGD surface loop is shorter than that of Ad2 and probably less flexible, hence more suitable for structural characterization of the Ad-integrin complex. The cryo-EM structures of the two virus-receptor complexes revealed a ring of integrin density above the penton base of each virus serotype. As expected, the integrin density in the Ad2 complex was diffuse while that in the Ad12 complex was better defined. The integrin consists of two discrete subdomains, a globular domain with an RGD-binding cleft similar to 20 Angstrom in diameter and a distal domain with extended, flexible tails. Kinetic analysis of Ad2 interactions with alpha(v)beta 5 indicated similar to 4.2 integrin molecules bound per penton base at close to saturation. These results suggest that the precise spatial arrangement of five RGD protrusions on the penton base promotes integrin clustering and the signaling events required for virus internalization.