Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3
Abstract 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...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62174-2 |
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| author | Gyunghee 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 |
| author_facet | Gyunghee 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 |
| author_sort | Gyunghee Jo |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-d4ce02f8521d470d847dcea2f30c8c3e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d4ce02f8521d470d847dcea2f30c8c3e2025-08-20T03:43:00ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-62174-2Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3Gyunghee Jo0Seiya Yamayoshi1Krystal M. Ma2Olivia Swanson3Jonathan L. Torres4James A. Ferguson5Monica L. Fernández-Quintero6Jiachen Huang7Jeffrey Copps8Alesandra J. Rodriguez9Jon M. Steichen10Yoshihiro Kawaoka11Julianna Han12Andrew B. Ward13Department of Integrative Structural and Computational Biology, The Scripps Research InstituteDivision of Virology, Institute of Medical Science, The University of TokyoDepartment of Immunology and Microbiology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Immunology and Microbiology, The Scripps Research InstituteDivision of Virology, Institute of Medical Science, The University of TokyoDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteAbstract 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.https://doi.org/10.1038/s41467-025-62174-2 |
| spellingShingle | Gyunghee 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 Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3 Nature Communications |
| title | Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3 |
| title_full | Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3 |
| title_fullStr | Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3 |
| title_full_unstemmed | Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3 |
| title_short | Structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in CDR H3 |
| title_sort | structural basis of broad protection against influenza virus by human antibodies targeting the neuraminidase active site via a recurring motif in cdr h3 |
| url | https://doi.org/10.1038/s41467-025-62174-2 |
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