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.
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Authors | Guntur Fibriansah, Joanne L Tan, Scott A Smith, Adamberage R de Alwis, Thiam-Seng Ng, Victor A Kostyuchenko, Kristie D Ibarra, Jiaqi Wang, Eva Harris, Aravinda de Silva, James E Crowe Jr, Shee-Mei Lok |
Journal | EMBO molecular medicine
(EMBO Mol Med)
Vol. 6
Issue 3
Pg. 358-71
(03 2014)
ISSN: 1757-4684 [Electronic] England |
PMID | 24421336
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antibodies, Monoclonal
- Antibodies, Neutralizing
- Antibodies, Viral
- Epitopes
- Immunoglobulin Fab Fragments
- Viral Envelope Proteins
- E protein TH Sman, Dengue virus
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Topics |
- Amino Acid Sequence
- Animals
- Antibodies, Monoclonal
(immunology, pharmacology, therapeutic use)
- Antibodies, Neutralizing
(immunology)
- Antibodies, Viral
(immunology)
- Cell Line
- Dengue
(drug therapy, veterinary)
- Dengue Virus
(metabolism)
- Epitopes
(chemistry, immunology)
- Humans
- Immunoglobulin Fab Fragments
(chemistry, immunology)
- Mice
- Molecular Dynamics Simulation
- Molecular Sequence Data
- Protein Structure, Tertiary
- Viral Envelope Proteins
(chemistry, immunology)
- Virus Internalization
(drug effects)
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