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Title: Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41
Author: Sabin, Charles
Corti, Davide
Buzon Redorta, Víctor
Seaman, Mike S.
Hulsik, David Lutje
Hinz, Andreas M.
Vanzetta, Fabrizia
Agatic, Gloria
Silacci, Chiara
Mainetti, Lara
Scarlatti, Gabriela
Sallusto, Federica
Weiss, Robin
Lanzavecchia, Antonio
Weissenhorn, Winfried
Keywords: Sida
Estructura cristal·lina (Sòlids)
Fusió membranària
AIDS (Disease)
Layer structure (Solids)
Membrane fusion
Issue Date: 18-Nov-2010
Publisher: Public Library of Science (PLoS)
Abstract: The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 Å resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for C-clade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool.
Note: Reproducció del document publicat a:
It is part of: PLoS Pathogens, 2010, vol. 6, num. 11, p. e1001195
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ISSN: 1553-7374
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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