title: A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins.
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.
authors.affiliation: 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.
authors.forename: Guntur
authors.initials: G
authors.lastname: Fibriansah
authors.affiliation: 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.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, CB#7292, 9024 Burnett Womack, Chapel Hill, North Carolina 27599-7292, USA.
authors.forename: Ruklanthi
authors.initials: R
authors.lastname: de Alwis
authors.affiliation: 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.
authors.forename: Thiam-Seng
authors.initials: TS
authors.lastname: Ng
authors.affiliation: 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.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Kostyuchenko
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, CB#7292, 9024 Burnett Womack, Chapel Hill, North Carolina 27599-7292, USA.
authors.forename: Ramesh S
authors.initials: RS
authors.lastname: Jadi
authors.affiliation: 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.
authors.forename: Petra
authors.initials: P
authors.lastname: Kukkaro
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, CB#7292, 9024 Burnett Womack, Chapel Hill, North Carolina 27599-7292, USA.
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
authors.affiliation: 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.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.affiliation: 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.
authors.forename: Shee-Mei
authors.initials: SM
authors.lastname: Lok
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D057134:Antibodies, Neutralizing / Q000737:chemistry*; D000914:Antibodies, Viral / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry; D002522:Chlorocebus aethiops; D020285:Cryoelectron Microscopy; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D005838:Genotype; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017386:Sequence Homology, Amino Acid; D065288:Serogroup; D014709:Vero Cells
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D008565:Membrane Proteins