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Journal of Virology, November 2009, p. 11491-11501, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01214-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cryo-Electron Microscopy Structure of an Adenovirus-Integrin Complex Indicates Conformational Changes in both Penton Base and Integrin{triangledown}

Steffen Lindert,1,2 Mariena Silvestry,1 Tina-Marie Mullen,3 Glen R. Nemerow,3 and Phoebe L. Stewart1*

Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, Tennessee 37232,1 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37212,2 Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, IMM-19, La Jolla, California 920373

Received 12 June 2009/ Accepted 27 August 2009

A structure of adenovirus type 12 (HAdV12) complexed with a soluble form of integrin {alpha}vβ5 was determined by cryo-electron microscopy (cryoEM) image reconstruction. Subnanometer resolution (8 Å) was achieved for the icosahedral capsid with moderate resolution (27 Å) for integrin density above each penton base. Modeling with {alpha}vβ3 and {alpha}IIbβ3 crystal structures indicates that a maximum of four integrins fit over the pentameric penton base. The close spacing (~60 Å) of the RGD protrusions on penton base precludes integrin binding in the same orientation to neighboring RGD sites. Flexible penton-base RGD loops and incoherent averaging of bound integrin molecules explain the moderate resolution observed for the integrin density. A model with four integrins bound to a penton base suggests that integrin might extend one RGD-loop in the direction that could induce a conformational change in the penton base involving clockwise untwisting of the pentamer. A global conformational change in penton base could be one step on the way to the release of Ad vertex proteins during cell entry. Comparison of the cryoEM structure with bent and extended models for the integrin ectodomain reveals that integrin adopts an extended conformation when bound to the Ad penton base, a multivalent viral ligand. These findings shed further light on the structural basis of integrin binding to biologically relevant ligands, as well as on the molecular events leading to HAdV cell entry.

* Corresponding author. Mailing address: Vanderbilt University Medical Center, Department of Molecular Physiology and Biophysics, 710 Light Hall, 2215 Garland Avenue, Nashville, TN 37232. Phone: (615) 322-7908. Fax: (615) 322-7236. E-mail: phoebe.stewart{at}vanderbilt.edu

{triangledown} Published ahead of print on 2 September 2009.

Journal of Virology, November 2009, p. 11491-11501, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01214-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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