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TitleA broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection.
Journal, issue, pagesCell Rep Med, Vol. 4, Issue 12, Page 101305, Year 2023
Publish dateDec 19, 2023
AuthorsLucas J Adams / Laura A VanBlargan / Zhuoming Liu / Pavlo Gilchuk / Haiyan Zhao / Rita E Chen / Saravanan Raju / Zhenlu Chong / Bradley M Whitener / Swathi Shrihari / Prashant N Jethva / Michael L Gross / James E Crowe / Sean P J Whelan / Michael S Diamond / Daved H Fremont /
PubMed AbstractMost neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal ...Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape.
External linksCell Rep Med / PubMed:38039973 / PubMed Central
MethodsEM (single particle)
Resolution3.13 Å
Structure data

25487

7sww

EMDB-25487, PDB-7sww:
SARS-CoV-2 Spike NTD in complex with neutralizing Fab SARS2-57 (local refinement)
Method: EM (single particle) / Resolution: 3.13 Å

25488

7swx

EMDB-25488, PDB-7swx:
SARS-CoV-2 Spike in complex with neutralizing Fab SARS2-57 (three down conformation)
Method: EM (single particle) / Resolution: 3.13 Å

Chemicals

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

Source
  • severe acute respiratory syndrome coronavirus 2
  • mus musculus (house mouse)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Glycoprotein / Antibody / Structural Genomics / Center for Structural Genomics of Infectious Diseases / CSGID / VIRAL PROTEIN-IMMUNE SYSTEM complex / Center for Structural Biology of Infectious Diseases / CSBID

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