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Structure paper

TitleAntibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry.
Journal, issue, pagesScience, Vol. 375, Issue 6579, Page 449-454, Year 2022
Publish dateJan 28, 2022
AuthorsYoung-Jun Park / Anna De Marco / Tyler N Starr / Zhuoming Liu / Dora Pinto / Alexandra C Walls / Fabrizia Zatta / Samantha K Zepeda / John E Bowen / Kaitlin R Sprouse / Anshu Joshi / Martina Giurdanella / Barbara Guarino / Julia Noack / Rana Abdelnabi / Shi-Yan Caroline Foo / Laura E Rosen / Florian A Lempp / Fabio Benigni / Gyorgy Snell / Johan Neyts / Sean P J Whelan / Herbert W Virgin / Jesse D Bloom / Davide Corti / Matteo Samuele Pizzuto / David Veesler /
PubMed AbstractUnderstanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against SARS-CoV-2 variants and future zoonotic sarbecoviruses. We describe the isolation and ...Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against SARS-CoV-2 variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades which use ACE2 as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta challenge in hamsters and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.
External linksScience / PubMed:34990214 / PubMed Central
MethodsEM (single particle)
Resolution3.2 Å
Structure data

25783

7tas

EMDB-25783, PDB-7tas:
SARS-CoV-2 spike in complex with the S2K146 neutralizing antibody Fab fragment (local refinement of the RBD and S2K146)
Method: EM (single particle) / Resolution: 3.2 Å

25784

7tat

EMDB-25784, PDB-7tat:
SARS-CoV-2 spike in complex with the S2K146 neutralizing antibody Fab fragment (two receptor-binding domains open)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-25785:
SARS-CoV-2 spike in complex with the S2K146 neutralizing antibody Fab fragment (three receptor-binding domains open)
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / SARS-CoV-2 / COVID-19 / spike glycoprotein / fusion protein / neutralizing antibodies / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / inhibitor / VIRAL PROTEIN-IMMUNE SYSTEM complex

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