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Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.

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 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.

SUBMITTER: Adams C

PROVIDER: S-EPMC9870165 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.

Adams Cameron C Carbaugh Derek L DL Shu Bo B Ng Thiam-Seng TS Castillo Izabella N IN Bhowmik Ryan R Segovia-Chumbez Bruno B Puhl Ana C AC Graham Stephen S Diehl Sean A SA Lazear Helen M HM Lok Shee-Mei SM de Silva Aravinda M AM Premkumar Lakshmanane L

PLoS pathogens 20230110 1

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 ...[more]

PMID: 36626401

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Dataset Information

Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.

Publications

Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.

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