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Science 12 June 2009:
Vol. 324. no. 5933, pp. 1444 - 1447
DOI: 10.1126/science.1170481
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Reports

Structure of Rotavirus Outer-Layer Protein VP7 Bound with a Neutralizing Fab

Scott T. Aoki,1 Ethan C. Settembre,1,* Shane D. Trask,1,{dagger} Harry B. Greenberg,2 Stephen C. Harrison,1,3,{ddagger} Philip R. Dormitzer1,*,{ddagger}

Rotavirus outer-layer protein VP7 is a principal target of protective antibodies. Removal of free calcium ions (Ca2+) dissociates VP7 trimers into monomers, releasing VP7 from the virion, and initiates penetration-inducing conformational changes in the other outer-layer protein, VP4. We report the crystal structure at 3.4 angstrom resolution of VP7 bound with the Fab fragment of a neutralizing monoclonal antibody. The Fab binds across the outer surface of the intersubunit contact, which contains two Ca2+ sites. Mutations that escape neutralization by other antibodies suggest that the same region bears the epitopes of most neutralizing antibodies. The monovalent Fab is sufficient to neutralize infectivity. We propose that neutralizing antibodies against VP7 act by stabilizing the trimer, thereby inhibiting the uncoating trigger for VP4 rearrangement. A disulfide-linked trimer is a potential subunit immunogen.

1 Laboratory of Molecular Medicine, Children’s Hospital, Boston, MA 02115, USA.
2 Department of Microbiology and Immunology and Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA, and VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
3 Howard Hughes Medical Institute, Children’s Hospital, Boston, MA 02115, USA.

* Present address: Novartis Vaccines and Diagnostics Inc., 350 Massachusetts Avenue, Cambridge, MA 02139, USA.

{dagger} Present address: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

{ddagger} To whom correspondence should be addressed. E-mail: harrison{at}crystal.harvard.edu (S.C.H.); philip.dormitzer{at}novartis.com (P.R.D.)

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
VP5* Rearranges when Rotavirus Uncoats.
J. D. Yoder, S. D. Trask, P. T. Vo, M. Binka, N. Feng, S. C. Harrison, H. B. Greenberg, and P. R. Dormitzer (2009)
J. Virol. 83, 11372-11377
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