7SCN

Structure of H1 NC99 influenza hemagglutinin bound to Fab 310-63E6

Summary for 7SCN

• Entry DOI: 10.2210/pdb7scn/pdb
• EMDB information: 25039
• Descriptor: Hemagglutinin HA1 chain, Hemagglutinin HA2 chain, 310-63E6 Fab, Heavy Chain, ... (5 entities in total)
• Functional Keywords: hemagglutinin, influenza, antibody, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Influenza A virus (strain A/New Zealand:South Canterbury/35/2000 H1N1); More
• Total number of polymer chains: 12
• Total formula weight: 266640.15

Authors

Ward, A.,Torrents de la Pena, A. (deposition date: 2021-09-28, release date: 2022-08-24, Last modification date: 2024-11-06)

Primary citation

Sangesland, M.,Torrents de la Pena, A.,Boyoglu-Barnum, S.,Ronsard, L.,Mohamed, F.A.N.,Moreno, T.B.,Barnes, R.M.,Rohrer, D.,Lonberg, N.,Ghebremichael, M.,Kanekiyo, M.,Ward, A.,Lingwood, D.
Allelic polymorphism controls autoreactivity and vaccine elicitation of human broadly neutralizing antibodies against influenza virus.
Immunity, 55:1693-1709.e8, 2022

PubMed Abstract: Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of group 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine (F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstrated that both alleles encode for human IAV bnAbs that employ structurally convergent modes of contact to the same epitope. To resolve differences in lineage expandability, we compared F54 versus L54 as substrate within humanized mice, where antibodies develop with human-like CDRH3 diversity but are restricted to single V genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supported elicitation of heterosubtypic serum bnAbs following immunization with a stalk-only nanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cells and autoreactive stalk antibodies that were cleared from B cell memory. Moreover, human stalk antibodies also demonstrated L54-dependent autoreactivity. Therefore, IGHV1-69 polymorphism, which is skewed ethnically, gates tolerance and vaccine expandability of influenza bnAbs.

PubMed: 35952670
DOI: 10.1016/j.immuni.2022.07.006

Experimental method

ELECTRON MICROSCOPY (3.02 Å)