7QA4

Crystal structure of stabilized H3N2 A/Hong Kong/1/1968 Hemagglutinin at 2.2 Angstrom

Summary for 7QA4

• Entry DOI: 10.2210/pdb7qa4/pdb
• Descriptor: Hemagglutinin, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: influenza, hemagglutinin, stabilized, fusion protein, unknown function, viral protein
• Biological source: Influenza A virus (strain A/Hong Kong/1/1968 H3N2)
• Total number of polymer chains: 1
• Total formula weight: 59761.06

Authors

Milder, F.J.,Langedijk, J.P.M. (deposition date: 2021-11-16, release date: 2022-02-02, Last modification date: 2022-03-30)

Primary citation

Milder, F.J.,Jongeneelen, M.,Ritschel, T.,Bouchier, P.,Bisschop, I.J.M.,de Man, M.,Veldman, D.,Le, L.,Kaufmann, B.,Bakkers, M.J.G.,Juraszek, J.,Brandenburg, B.,Langedijk, J.P.M.
Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions.
Proc.Natl.Acad.Sci.USA, 119:-, 2022

PubMed Abstract: For an efficacious vaccine immunogen, influenza hemagglutinin (HA) needs to maintain a stable quaternary structure, which is contrary to the inherently dynamic and metastable nature of class I fusion proteins. In this study, we stabilized HA with three substitutions within its pH-sensitive regions where the refolding starts. An X-ray structure reveals how these substitutions stabilize the intersubunit β-sheet in the base and form an interprotomeric aliphatic layer across the stem while the native prefusion HA fold is retained. The identification of the stabilizing substitutions increases our understanding of how the pH sensitivity is structurally accomplished in HA and possibly other pH-sensitive class I fusion proteins. Our stabilization approach in combination with the occasional back mutation of rare amino acids to consensus results in well-expressing stable trimeric HAs. This repair and stabilization approach, which proves broadly applicable to all tested influenza A HAs of group 1 and 2, will improve the developability of influenza vaccines based on different types of platforms and formats and can potentially improve efficacy.

PubMed: 35131851
DOI: 10.1073/pnas.2115379119

Experimental method

X-RAY DIFFRACTION (2.19 Å)