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Nat Commun. 2015 Feb 20;6:6341. doi: 10.1038/ncomms7341.

A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins.

Author information

1
1] Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore [2] Centre for BioImaging Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117557, Singapore.
2
1] Department of Medicine, Vanderbilt University, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, Tennessee 37232-2358, USA [2] The Vanderbilt Vaccine Center, Vanderbilt University,Vanderbilt University Medical Center, 11475 MRB IV-2213 Garland Avenue, Nashville, Tennessee 37232-0417, USA.
3
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, CB#7292, 9024 Burnett Womack, Chapel Hill, North Carolina 27599-7292, USA.
4
1] The Vanderbilt Vaccine Center, Vanderbilt University,Vanderbilt University Medical Center, 11475 MRB IV-2213 Garland Avenue, Nashville, Tennessee 37232-0417, USA [2] Departments of Pediatrics and Pathology, Microbiology and Immunology, Vanderbilt University, Vanderbilt University Medical Center, 11475 MRB IV-2213 Garland Avenue, Nashville, Tennessee 37232-0417, USA.

Abstract

Dengue virus (DENV) infects ~400 million people annually. There is no licensed vaccine or therapeutic drug. Only a small fraction of the total DENV-specific antibodies in a naturally occurring dengue infection consists of highly neutralizing antibodies. Here we show that the DENV-specific human monoclonal antibody 5J7 is exceptionally potent, neutralizing 50% of virus at nanogram-range antibody concentration. The 9 Å resolution cryo-electron microscopy structure of the Fab 5J7-DENV complex shows that a single Fab molecule binds across three envelope proteins and engages three functionally important domains, each from a different envelope protein. These domains are critical for receptor binding and fusion to the endosomal membrane. The ability to bind to multiple domains allows the antibody to fully coat the virus surface with only 60 copies of Fab, that is, half the amount compared with other potent antibodies. Our study reveals a highly efficient and unusual mechanism of molecular recognition by an antibody.

PMID:
25698059
PMCID:
PMC4346626
DOI:
10.1038/ncomms7341
[Indexed for MEDLINE]
Free PMC Article

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