title: A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface.
abstract: Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400 million people annually. Previous studies have indicated most human monoclonal antibodies (HMAbs) from dengue patients are cross-reactive and poorly neutralizing. Rare neutralizing HMAbs are usually serotype-specific and bind to quaternary structure-dependent epitopes. We determined the structure of DENV1 complexed with Fab fragments of a highly potent HMAb 1F4 to 6 Å resolution by cryo-EM. Although HMAb 1F4 appeared to bind to virus and not E proteins in ELISAs in the previous study, our structure showed that the epitope is located within an envelope (E) protein monomer, and not across neighboring E proteins. The Fab molecules bind to domain I (DI), and DI-DII hinge of the E protein. We also showed that HMAb 1F4 can neutralize DENV at different stages of viral entry in a cell type and receptor dependent manner. The structure reveals the mechanism by which this potent and specific antibody blocks viral infection.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore City, Singapore.
authors.forename: Guntur
authors.initials: G
authors.lastname: Fibriansah
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Tan
authors.forename: Scott A
authors.initials: SA
authors.lastname: Smith
authors.forename: Adamberage R
authors.initials: AR
authors.lastname: de Alwis
authors.forename: Thiam-Seng
authors.initials: TS
authors.lastname: Ng
authors.forename: Victor A
authors.initials: VA
authors.lastname: Kostyuchenko
authors.forename: Kristie D
authors.initials: KD
authors.lastname: Ibarra
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Wang
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.forename: Aravinda
authors.initials: A
authors.lastname: de Silva
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.forename: Shee-Mei
authors.initials: SM
authors.lastname: Lok
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D002460:Cell Line; D003715:Dengue / Q000188:drug therapy / Q000662:veterinary; D003716:Dengue Virus / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D014759:Viral Envelope Proteins; C072281:E protein TH Sman, Dengue virus