8DV6

Zika virus envelope protein structure in complex with a potent Human mAb

This is a non-PDB format compatible entry.

Summary for 8DV6

• Entry DOI: 10.2210/pdb8dv6/pdb
• Descriptor: Envelope protein E, mAb Fab Heavy Chain, mAb Fab Light Chain (3 entities in total)
• Functional Keywords: zika virus, envelope protein, neutralizing antibody, neutralization mechanism, flavivirus, viral protein, viral protein-immune system complex
• Biological source: Zika virus ZIKV/Human/Cambodia/FSS13025/2010 (ZIKV); More
• Total number of polymer chains: 6
• Total formula weight: 188458.73

Authors

Cameron, A.,Puhl, A.C.,deSilva, A.M.,Premkumar, L. (deposition date: 2022-07-28, release date: 2023-01-04, Last modification date: 2024-11-20)

Primary citation

Adams, C.,Carbaugh, D.L.,Shu, B.,Ng, T.S.,Castillo, I.N.,Bhowmik, R.,Segovia-Chumbez, B.,Puhl, A.C.,Graham, S.,Diehl, S.A.,Lazear, H.M.,Lok, S.M.,de Silva, A.M.,Premkumar, L.
Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.
Plos Pathog., 19:e1010814-e1010814, 2023

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 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.

PubMed: 36626401
DOI: 10.1371/journal.ppat.1010814

Experimental method

X-RAY DIFFRACTION (3.38 Å)