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Journal of Virology, August 1999, p. 6759-6768, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Structure of Adenovirus Complexed with Its Internalization Receptor, alpha vbeta 5 Integrin

Charles Y. Chiu,1 Patricia Mathias,2 Glen R. Nemerow,2,* and Phoebe L. Stewart1,*

Department of Molecular and Medical Pharmacology, Crump Institute for Biological Imaging, University of California---Los Angeles School of Medicine, Los Angeles, California 90095,1 and Department of Immunology, The Scripps Research Institute, La Jolla, California 920372

Received 19 February 1999/Accepted 21 April 1999

The three-dimensional structure of soluble recombinant integrin alpha vbeta 5 bound to human adenovirus types 2 and 12 (Ad2 and -12) has been determined at ~21-Å resolution by cryoelectron microscopy (cryo-EM). The alpha vbeta 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 ~20 Å in diameter and a distal domain with extended, flexible tails. Kinetic analysis of Ad2 interactions with alpha vbeta 5 indicated ~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.

* Corresponding author. Mailing address for Phoebe L. Stewart: Department of Molecular and Medical Pharmacology, UCLA School of Medicine, A-324 CIBI, Box 951770, Los Angeles, CA 90095-1770. Phone: (310) 206-7055. Fax: (310) 206-8975. E-mail: pstewart{at}mednet.ucla.edu. Mailing address for Glen R. Nemerow: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037. Phone: (619) 784-8072. Fax: (619) 784-8472. E-mail: gnemerow{at}scripps.edu.

Journal of Virology, August 1999, p. 6759-6768, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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