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TitleStructural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7067, Year 2025
Publish dateAug 1, 2025
AuthorsGyunghee Jo / Seiya Yamayoshi / Krystal M Ma / Olivia Swanson / Jonathan L Torres / James A Ferguson / Monica L Fernández-Quintero / Jiachen Huang / Jeffrey Copps / Alesandra J Rodriguez / Jon M Steichen / Yoshihiro Kawaoka / Julianna Han / Andrew B Ward /
PubMed AbstractInfluenza viruses evolve rapidly, driving seasonal epidemics and posing global pandemic threats. While neuraminidase (NA) has emerged as a vaccine target, shared molecular features of NA antibody ...Influenza viruses evolve rapidly, driving seasonal epidemics and posing global pandemic threats. While neuraminidase (NA) has emerged as a vaccine target, shared molecular features of NA antibody responses are still not well understood. Here, we describe cryo-electron microscopy structures of the broadly protective human antibody DA03E17, which was previously identified from an H1N1-infected donor, in complex with NA from A/H1N1, A/H3N2, and B/Victoria-lineage viruses. DA03E17 targets the highly conserved NA active site using its long CDR H3, which features a DR (Asp-Arg) motif that engages catalytic residues and mimics sialic acid interactions. We further demonstrate that this motif is conserved among several NA active site-targeting antibodies, indicating a common receptor mimicry strategy. We also identified BCR sequences containing this DR motif across all donors in a healthy human repertoire database, suggesting that such precursors may be relatively common and have vaccine targeting potential. Our findings reveal shared molecular features in NA active site-targeting antibodies that can be harnessed to design broad, immune-focused influenza vaccines.
External linksNat Commun / PubMed:40750588 / PubMed Central
MethodsEM (single particle)
Resolution2.47 - 3.2 Å
Structure data

46041

9cye

EMDB-46041, PDB-9cye:
Cryo-EM structure of DA03E17 Fab in complex with influenza virus neuraminidase from A/California/07/2009 (H1N1)
Method: EM (single particle) / Resolution: 2.7 Å

46042

9cyf

EMDB-46042, PDB-9cyf:
Cryo-EM structure of DA03E17 Fab in complex with influenza virus neuraminidase from A/Kansas/14/2017 (H3N2)
Method: EM (single particle) / Resolution: 2.86 Å

46043

9cyg

EMDB-46043, PDB-9cyg:
Cryo-EM structure of influenza virus neuraminidase from A/Kansas/14/2017 (H3N2)
Method: EM (single particle) / Resolution: 2.75 Å

46044

9cyh

EMDB-46044, PDB-9cyh:
Cryo-EM structure of DA03E17 Fab in complex with influenza virus neuraminidase from B/Colorado/06/2017
Method: EM (single particle) / Resolution: 2.47 Å

46045

9cyi

EMDB-46045, PDB-9cyi:
Cryo-EM structure of 1G01 IgG in complex with influenza virus neuraminidase from A/Kansas/14/2017 (H3N2)
Method: EM (single particle) / Resolution: 3.2 Å

46046

9cyj

EMDB-46046, PDB-9cyj:
Cryo-EM structure of FNI9 IgG in complex with influenza virus neuraminidase from A/Kansas/14/2017 (H3N2)
Method: EM (single particle) / Resolution: 2.97 Å

70108

9o4n

EMDB-70108, PDB-9o4n:
Cryo-EM structure of CR12042 Fab in complex with influenza virus neuraminidase from A/California/07/2009 (H1N1)
Method: EM (single particle) / Resolution: 2.48 Å

70109

9o4o

EMDB-70109, PDB-9o4o:
Cryo-EM structure of CR12044 Fab in complex with influenza virus neuraminidase from A/California/07/2009 (H1N1)
Method: EM (single particle) / Resolution: 2.53 Å

70110

9o4p

EMDB-70110, PDB-9o4p:
Cryo-EM structure of AF9C-GL Fab in complex with influenza virus neuraminidase from A/California/07/2009 (H1N1)
Method: EM (single particle) / Resolution: 2.55 Å

70111

9o4q

EMDB-70111, PDB-9o4q:
Cryo-EM structure of Z1A11-GL Fab in complex with influenza virus neuraminidase from A/California/07/2009 (H1N1)
Method: EM (single particle) / Resolution: 2.76 Å

Chemicals

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

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
  • influenza a virus (a/california/07/2009(h1n1))
  • influenza a virus
  • influenza b virus (b/colorado/06/2017)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Neuraminidase / Hydrolase / Antibody complex / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex

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