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Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein
Authors:
Ilona
Rissanen
(Wellcome Centre for Human Genetics, University of Oxford; Helsinki Institute of Life Science HiLIFE, University of Helsinki)
,
Robert
Stass
(Wellcome Centre for Human Genetics, University of Oxford)
,
Stefanie A.
Krumm
(King's College London, Guy's Hospital)
,
Jeffrey
Seow
(King's College London, Guy's Hospital)
,
Ruben J. G.
Hulswit
(Wellcome Centre for Human Genetics, University of Oxford)
,
Guido C.
Paesen
(Wellcome Centre for Human Genetics, University of Oxford)
,
Jussi
Hepojoki
(University of Zürich; University of Helsinki)
,
Olli
Vapalahti
(University of Helsinki and HUSLAB, Helsinki University Hospital)
,
Åke
Lundkvist
(Uppsala University)
,
Olivier
Reynard
(CIRI, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, Université Lyon)
,
Viktor
Volchkov
(CIRI, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, Université Lyon)
,
Katie J
Doores
(King's College London, Guy's Hospital)
,
Juha T.
Huiskonen
(Wellcome Centre for Human Genetics, University of Oxford; Helsinki Institute of Life Science HiLIFE, University of Helsinki)
,
Thomas A.
Bowden
(Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Elife
, VOL 9
State:
Published (Approved)
Published:
December 2020
Diamond Proposal Number(s):
19946

Abstract: The intricate lattice of Gn and Gc glycoprotein spike complexes on the hantavirus envelope facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Through study of a neutralizing monoclonal antibody termed mAb P-4G2, which neutralizes the zoonotic pathogen Puumala virus (PUUV), we provide a molecular-level basis for antibody-mediated targeting of the hantaviral glycoprotein lattice. Crystallographic analysis demonstrates that P-4G2 binds to a multi-domain site on PUUV Gc and may preclude fusogenic rearrangements of the glycoprotein that are required for host-cell entry. Furthermore, cryo-electron microscopy of PUUV-like particles in the presence of P-4G2 reveals a lattice-independent configuration of the Gc, demonstrating that P-4G2 perturbs the (Gn-Gc)4 lattice. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I24-Microfocus Macromolecular Crystallography
Documents:
elife-58242-v1.pdf