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Structures of complexes formed by H5 influenza hemagglutinin with a potent broadly neutralizing human monoclonal antibody

DOI: 10.1073/pnas.1510816112 DOI Help
PMID: 26170284 PMID Help

Authors: Xiaoli Xiong (The Francis Crick Institute) , Davide Corti (Institute for Research in Biomedicine) , Junfeng Liu (China Agricultural University) , Debora Pinna (Institute for Research in Biomedicine) , Mathilde Foglierini (Institute for Research in Biomedicine) , Lesley J. Calder (The Francis Crick Institute) , Stephen R. Martin (The Francis Crick Institute) , Yi Pu Lin (The Francis Crick Institute) , Phil Walker (The Francis Crick Institute) , Patrick J. Collins (The Francis Crick Institute) , Isabella Monne (Istituto Zooprofilattico Sperimentale delle Venezie) , Amorsolo L. Suguitan (National Institute of Allergy and Infectious Diseases, National Institutes of Health) , Celia Santos (National Institute of Allergy and Infectious Diseases, National Institutes of Health) , Nigel J. Temperton (University of Kent) , Kanta Subbarao (National Institute of Allergy and Infectious Diseases, National Institutes of Health) , Antonio Lanzavecchia (Institute for Research in Biomedicine) , Steven Gamblin (The Francis Crick Institute) , John J. Skehel (The Francis Crick Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 112 (30) , PAGES 9430 - 9435

State: Published (Approved)
Published: July 2015
Diamond Proposal Number(s): 7707 , 9826

Open Access Open Access

Abstract: H5N1 avian influenza viruses remain a threat to public health mainly because they can cause severe infections in humans. These viruses are widespread in birds, and they vary in antigenicity forming three major clades and numerous antigenic variants. The most important features of the human monoclonal antibody FLD194 studied here are its broad specificity for all major clades of H5 influenza HAs, its high affinity, and its ability to block virus infection, in vitro and in vivo. As a consequence, this antibody may be suitable for anti-H5 therapy and as a component of stockpiles, together with other antiviral agents, for health authorities to use if an appropriate vaccine was not available. Our mutation and structural analyses indicate that the antibody recognizes a relatively conserved site near the membrane distal tip of HA, near to, but distinct from, the receptor-binding site. Our analyses also suggest that the mechanism of infectivity neutralization involves prevention of receptor recognition as a result of steric hindrance by the Fc part of the antibody. Structural analyses by EM indicate that three Fab fragments are bound to each HA trimer. The structure revealed by X-ray crystallography is of an HA monomer bound by one Fab. The monomer has some similarities to HA in the fusion pH conformation, and the monomer’s formation, which results from the presence of isopropanol in the crystallization solvent, contributes to considerations of the process of change in conformation required for membrane fusion.

Journal Keywords: Influenza Virus; Neutralizing Antibody; H5N1

Diamond Keywords: Influenza; Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/09/2015 16:33

Documents:
pnas.1510816112.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)