Paper Citing NAMD - Abstract
Fibriansah, Guntur; Tan, Joanne L.; Smith, Scott A.; de Alwis, Adamberage R.; Thiam-Seng Ng; Kostyuchenko, Victor A.; Ibarra, Kristie D.; Wang, Jiaqi; Harris, Eva; de Silva, Aravinda; Crowe, James E., Jr.; Lok, Shee-Mei
A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface
EMBO MOLECULAR MEDICINE, 6:358-371, MAR 2014
Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400million 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 angstrom 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.
