Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion
Rupert J. Russell,Philip S. Kerry,D.J. Stevens,David A. Steinhauer,Stephen R. Martin,Steven J. Gamblin,John J. Skehel +6 more
TLDR
The structure of HA in complex with a known inhibitor of membrane fusion and virus infectivity, tert-butyl hydroquinone (TBHQ), shows that the inhibitor binds in a hydrophobic pocket formed at an interface between HA monomers that stabilizes the neutral pH structure.Abstract:
The influenza surface glycoprotein hemagglutinin (HA) is a potential target for antiviral drugs because of its key roles in the initial stages of infection: receptor binding and the fusion of virus and cell membranes. The structure of HA in complex with a known inhibitor of membrane fusion and virus infectivity, tert-butyl hydroquinone (TBHQ), shows that the inhibitor binds in a hydrophobic pocket formed at an interface between HA monomers. Occupation of this site by TBHQ stabilizes the neutral pH structure through intersubunit and intrasubunit interactions that presumably inhibit the conformational rearrangements required for membrane fusion. The nature of the binding site suggests routes for the chemical modification of TBHQ that could lead to the development of more potent inhibitors of membrane fusion and potential anti-influenza drugs.read more
Citations
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Antibody Recognition of a Highly Conserved Influenza Virus Epitope
Damian C. Ekiert,Gira Bhabha,Marc-André Elsliger,Robert H. E. Friesen,Mandy Jongeneelen,Mark Throsby,Jaap Goudsmit,Ian A. Wilson +7 more
TL;DR: TheCR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.
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Structural and Functional Bases for Broad-Spectrum Neutralization of Avian and Human Influenza A Viruses
Jianhua Sui,William C. Hwang,Sandra Elizabeth Pérez,Ge Wei,Daniel Aird,Li-Mei Chen,Eugenio Santelli,Boguslaw Stec,Greg Cadwell,Maryam Ali,Hongquan Wan,Akikazu Murakami,Anuradha Yammanuru,Thomas Han,Nancy J. Cox,Laurie A. Bankston,Ruben O. Donis,Robert C. Liddington,Wayne A. Marasco +18 more
TL;DR: The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion, and suggests that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.
Journal ArticleDOI
A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins
Davide Corti,Jarrod Voss,Steven J. Gamblin,Giosiana Codoni,Annalisa Macagno,David Jarrossay,Sebastien G. Vachieri,Debora Pinna,Andrea Minola,Fabrizia Vanzetta,Chiara Silacci,Blanca Fernandez-Rodriguez,Gloria Agatic,Siro Bianchi,Isabella Giacchetto-Sasselli,Lesley J. Calder,Federica Sallusto,Patrick J. Collins,Lesley F. Haire,Nigel J. Temperton,Johannes P. M. Langedijk,John J. Skehel,Antonio Lanzavecchia +22 more
TL;DR: An antibody able to broadly neutralize both group 1 and group 2 influenza A viruses—and its target epitope—are identified and may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.
Journal ArticleDOI
Influenza Hemagglutinin and Neuraminidase Membrane Glycoproteins
Steven J. Gamblin,John J. Skehel +1 more
TL;DR: Resistance to one of the two main antiviral drugs is differentially acquired by the two distinct subsets of neuraminidase as a consequence of structural differences in the enzyme active site between the two phylogenetic groups.
Journal ArticleDOI
Reliable B cell epitope predictions: impacts of method development and improved benchmarking.
TL;DR: An updated version of the DiscoTope method incorporating a novel spatial neighborhood definition and half-sphere exposure as surface measure is presented, demonstrating that given proper benchmark definitions, B-cell epitope prediction methods achieve highly significant predictive performances suggesting these tools to be a powerful asset in rational epitope discovery.
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