4M5Z: Crystal Structure Of Broadly Neutralizing Antibody 5j8 Bound To 2009 Pandemic Influenza Hemagglutinin, Ha1 Subunit

Citation:
Abstract
Influenza virus is a global health concern due to its unpredictable pandemic potential. This potential threat was realized in 2009 when an H1N1 virus emerged that resembled the 1918 virus in antigenicity but fortunately was not nearly as deadly. 5J8 is a human antibody that potently neutralizes a broad spectrum of H1N1 viruses, including the 1918 and 2009 pandemic viruses. Here, we present the crystal structure of 5J8 Fab in complex with a bacterially expressed and refolded globular head domain from the hemagglutinin (HA) of the A/California/07/2009 (H1N1) pandemic virus. 5J8 recognizes a conserved epitope in and around the receptor binding site (RBS), and its HCDR3 closely mimics interactions of the sialic acid receptor. Electron microscopy (EM) reconstructions of 5J8 Fab in complex with an HA trimer from a 1986 H1 strain and with an engineered stabilized HA trimer from the 2009 H1 pandemic virus showed a similar mode of binding. As for other characterized RBS-targeted antibodies, 5J8 uses avidity to extend its breadth and affinity against divergent H1 strains. 5J8 selectively interacts with HA insertion residue 133a, which is conserved in pandemic H1 strains and has precluded binding of other RBS-targeted antibodies. Thus, the RBS of divergent HAs is targeted by 5J8 and adds to the growing arsenal of common recognition motifs for design of therapeutics and vaccines. Moreover, consistent with previous studies, the bacterially expressed H1 HA properly refolds, retaining its antigenic structure, and presents a low-cost and rapid alternative for engineering and manufacturing candidate flu vaccines.
PDB ID: 4M5ZDownload
MMDB ID: 113775
PDB Deposition Date: 2013/8/8
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 2.25  Å
Source Organism:
Influenza A virus
Similar Structures:
Biological Unit for 4M5Z: trimeric; determined by author
Molecular Components in 4M5Z
Label Count Molecule
Proteins (3 molecules)
1
Hemagglutinin HA1 Chain
Molecule annotation
1
FAB 5J8 Heavy Chain
Molecule annotation
1
FAB 5J8 Light Chain
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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