Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein

DOI: 10.7554/eLife.58242

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