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-Structure paper
Title | Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus. |
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Journal, issue, pages | PLoS Pathog, Vol. 19, Issue 1, Page e1010814, Year 2023 |
Publish date | Jan 10, 2023 |
Authors | Cameron Adams / Derek L Carbaugh / Bo Shu / Thiam-Seng Ng / Izabella N Castillo / Ryan Bhowmik / Bruno Segovia-Chumbez / Ana C Puhl / Stephen Graham / Sean A Diehl / Helen M Lazear / Shee-Mei Lok / Aravinda M de Silva / Lakshmanane Premkumar / |
PubMed Abstract | We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing ...We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing human monoclonal antibody (mAb G9E) with Zika virus (ZIKV) by both X-ray crystallography and cryo-electron microscopy. Flavivirus envelope (E) glycoproteins are present as homodimers on the virion surface, and G9E bound to a quaternary structure epitope spanning both E protomers forming a homodimer. As G9E mainly neutralized ZIKV by blocking a step after viral attachment to cells, we tested if the neutralization mechanism of G9E was dependent on the mAb cross-linking E molecules and blocking low-pH triggered conformational changes required for viral membrane fusion. We introduced targeted mutations to the G9E paratope to create recombinant antibodies that bound to the ZIKV envelope without cross-linking E protomers. The G9E paratope mutants that bound to a restricted epitope on one protomer poorly neutralized ZIKV compared to the wild-type mAb, demonstrating that the neutralization mechanism depended on the ability of G9E to cross-link E proteins. In cell-free low pH triggered viral fusion assay, both wild-type G9E, and epitope restricted paratope mutant G9E bound to ZIKV but only the wild-type G9E blocked fusion. We propose that, beyond antibody binding strength, the ability of human antibodies to cross-link E-proteins is a critical determinant of flavivirus neutralization potency. |
External links | PLoS Pathog / PubMed:36626401 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 3.38 - 5.9 Å |
Structure data | EMDB-33718, PDB-7yar: PDB-8dv6: |
Source |
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Keywords | VIRUS / virus complexed with antibody / VIRAL PROTEIN / Zika virus / envelope protein / neutralizing antibody / neutralization mechanism / flavivirus / VIRAL PROTEIN-Immune System complex |