EMD-26653

Single-particle
2.77 Å
EMD-26653 Deposition: 13/04/2022
Map released: 02/11/2022
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-26653

Native Lassa glycoprotein in complex with neutralizing antibodies 8.9F and 37.2D

EMD-26653

Single-particle
2.77 Å
EMD-26653 Deposition: 13/04/2022
Map released: 02/11/2022
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Lassa virus
Sample: Native Lassa glycoprotein in complex with 8.9F-scFv and 37.2D-scFv
Fitted models: 7uot (Avg. Q-score: 0.559)

Deposition Authors: Li H , Saphire EO
A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus.
PUBMED: 36288283
DOI: doi:10.1126/scitranslmed.abq0991
ISSN: 1946-6242
Abstract:
Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.