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Proc Natl Acad Sci USA. Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354
Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354 (PNAS, abstract, edited)
[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/107/44/18950.short?rss=1">Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354 ? PNAS</cite>. Abstract, edited.]
Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354
1. B?rbel Kaufmann a, 2. Matthew R. Vogt b, 3. Jaap Goudsmit c, 4. Heather A. Holdaway a, 5. Anastasia A. Aksyuk a, 6. Paul R. Chipman a, 7. Richard J. Kuhn a, 8. Michael S. Diamond b,d,e, and 9. Michael G. Rossmann a,1
Author Affiliations
1. a Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-2054;
2. Departments of bPathology and Immunology,
3. d Molecular Microbiology, and
4. e Medicine, The Washington University School of Medicine, St. Louis, MO 63110; and
5. c Crucell Holland BV, 2301 CA Leiden, The Netherlands
1. Edited by Charles M. Rice, The Rockefeller University, New York, NY, and approved September 24, 2010 (received for review July 27, 2010)
Abstract
Many flaviviruses are significant human pathogens, with the humoral immune response playing an essential role in restricting infection and disease. CR4354, a human monoclonal antibody isolated from a patient, neutralizes West Nile virus (WNV) infection at a postattachment stage in the viral life-cycle. Here, we determined the structure of WNV complexed with Fab fragments of CR4354 using cryoelectron microscopy. The outer glycoprotein shell of a mature WNV particle is formed by 30 rafts of three homodimers of the viral surface protein E. CR4354 binds to a discontinuous epitope formed by protein segments from two neighboring E molecules, but does not cause any detectable structural disturbance on the viral surface. The epitope occurs at two independent positions within an icosahedral asymmetric unit, resulting in 120 binding sites on the viral surface. The cross-linking of the six E monomers within one raft by four CR4354 Fab fragments suggests that the antibody neutralizes WNV by blocking the pH-induced rearrangement of the E protein required for virus fusion with the endosomal membrane.
* antibody
* cryoelectron microscopy
* flavivirus
Footnotes
* 1 To whom correspondence should be addressed. E-mail: mr@purdue.edu.
* Author contributions: B.K. and M.G.R. designed research; B.K., M.R.V., H.A.H., A.A.A., and P.R.C. performed research; J.G. contributed new reagents/analytic tools; B.K. analyzed data; and B.K., R.J.K., M.S.D., and M.G.R. wrote the paper.
* The authors declare no conflict of interest.
* Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3N9G and 3IYW). The cryoEM density map of the WNV?Fab complex have been deposited in the Electron Microscopy Data Bank (accession no. EMD-5190), and complete coding regions have been deposited in the GenBank database (accession nos. FB580561.1 and FB580565.1).
* This article is a PNAS Direct Submission.
* This article contains supporting information online at https://www.pnas.org/lookup/suppl/do...DCSupplemental.
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[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/107/44/18950.short?rss=1">Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354 ? PNAS</cite>. Abstract, edited.]
Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354
1. B?rbel Kaufmann a, 2. Matthew R. Vogt b, 3. Jaap Goudsmit c, 4. Heather A. Holdaway a, 5. Anastasia A. Aksyuk a, 6. Paul R. Chipman a, 7. Richard J. Kuhn a, 8. Michael S. Diamond b,d,e, and 9. Michael G. Rossmann a,1
Author Affiliations
1. a Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-2054;
2. Departments of bPathology and Immunology,
3. d Molecular Microbiology, and
4. e Medicine, The Washington University School of Medicine, St. Louis, MO 63110; and
5. c Crucell Holland BV, 2301 CA Leiden, The Netherlands
1. Edited by Charles M. Rice, The Rockefeller University, New York, NY, and approved September 24, 2010 (received for review July 27, 2010)
Abstract
Many flaviviruses are significant human pathogens, with the humoral immune response playing an essential role in restricting infection and disease. CR4354, a human monoclonal antibody isolated from a patient, neutralizes West Nile virus (WNV) infection at a postattachment stage in the viral life-cycle. Here, we determined the structure of WNV complexed with Fab fragments of CR4354 using cryoelectron microscopy. The outer glycoprotein shell of a mature WNV particle is formed by 30 rafts of three homodimers of the viral surface protein E. CR4354 binds to a discontinuous epitope formed by protein segments from two neighboring E molecules, but does not cause any detectable structural disturbance on the viral surface. The epitope occurs at two independent positions within an icosahedral asymmetric unit, resulting in 120 binding sites on the viral surface. The cross-linking of the six E monomers within one raft by four CR4354 Fab fragments suggests that the antibody neutralizes WNV by blocking the pH-induced rearrangement of the E protein required for virus fusion with the endosomal membrane.
* antibody
* cryoelectron microscopy
* flavivirus
Footnotes
* 1 To whom correspondence should be addressed. E-mail: mr@purdue.edu.
* Author contributions: B.K. and M.G.R. designed research; B.K., M.R.V., H.A.H., A.A.A., and P.R.C. performed research; J.G. contributed new reagents/analytic tools; B.K. analyzed data; and B.K., R.J.K., M.S.D., and M.G.R. wrote the paper.
* The authors declare no conflict of interest.
* Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3N9G and 3IYW). The cryoEM density map of the WNV?Fab complex have been deposited in the Electron Microscopy Data Bank (accession no. EMD-5190), and complete coding regions have been deposited in the GenBank database (accession nos. FB580561.1 and FB580565.1).
* This article is a PNAS Direct Submission.
* This article contains supporting information online at https://www.pnas.org/lookup/suppl/do...DCSupplemental.
-
------