James Crowe
Faculty Member
Last active: 3/31/2020

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

Fibriansah G, Tan JL, Smith SA, de Alwis R, Ng TS, Kostyuchenko VA, Jadi RS, Kukkaro P, de Silva AM, Crowe JE, Lok SM
Nat Commun. 2015 6: 6341

PMID: 25698059 · PMCID: PMC4346626 · DOI:10.1038/ncomms7341

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.

MeSH Terms (24)

Amino Acid Sequence Animals Antibodies, Monoclonal Antibodies, Neutralizing Antibodies, Viral Cell Membrane Chlorocebus aethiops Cryoelectron Microscopy Dengue Dengue Virus Enzyme-Linked Immunosorbent Assay Epitopes Genotype Humans Immunoglobulin Fab Fragments Membrane Proteins Mice Molecular Sequence Data Neutralization Tests Protein Binding Protein Structure, Quaternary Sequence Homology, Amino Acid Serogroup Vero Cells

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