Probing altered receptor specificities of antigenically drifting human H3N2 viruses by chemoenzymatic synthesis, NMR, and modeling

Luca Unione (), Augustinus N. A. Ammerlaan, Gerlof P. Bosman, Elif Uslu, Ruonan Liang, Frederik Broszeit, Roosmarijn Woude, Yanyan Liu, Shengzhou Ma, Lin Liu, Marcos Gómez-Redondo, Iris A. Bermejo, Pablo Valverde, Tammo Diercks, Ana Ardá, Robert P. Vries () and Geert-Jan Boons ()
Additional contact information
Luca Unione: Utrecht University
Augustinus N. A. Ammerlaan: Utrecht University
Gerlof P. Bosman: Utrecht University
Elif Uslu: Utrecht University
Ruonan Liang: Utrecht University
Frederik Broszeit: Utrecht University
Roosmarijn Woude: Utrecht University
Yanyan Liu: Utrecht University
Shengzhou Ma: University of Georgia
Lin Liu: University of Georgia
Marcos Gómez-Redondo: Basque Research & Technology Alliance (BRTA)
Iris A. Bermejo: Basque Research & Technology Alliance (BRTA)
Pablo Valverde: Basque Research & Technology Alliance (BRTA)
Tammo Diercks: Basque Research & Technology Alliance (BRTA)
Ana Ardá: Basque Research & Technology Alliance (BRTA)
Robert P. Vries: Utrecht University
Geert-Jan Boons: Utrecht University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Prototypic receptors for human influenza viruses are N-glycans carrying α2,6-linked sialosides. Due to immune pressure, A/H3N2 influenza viruses have emerged with altered receptor specificities that bind α2,6-linked sialosides presented on extended N-acetyl-lactosamine (LacNAc) chains. Here, binding modes of such drifted hemagglutinin’s (HAs) are examined by chemoenzymatic synthesis of N-glycans having 13C-labeled monosaccharides at strategic positions. The labeled glycans are employed in 2D STD-1H by 13C-HSQC NMR experiments to pinpoint which monosaccharides of the extended LacNAc chain engage with evolutionarily distinct HAs. The NMR data in combination with computation and mutagenesis demonstrate that mutations distal to the receptor binding domain of recent HAs create an extended binding site that accommodates with the extended LacNAc chain. A fluorine containing sialoside is used as NMR probe to derive relative binding affinities and confirms the contribution of the extended LacNAc chain for binding.

Date: 2024
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DOI: 10.1038/s41467-024-47344-y

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