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Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies

View ORCID ProfileWeng M Ng, View ORCID ProfileSofiya Fedosyuk, View ORCID ProfileSolomon English, View ORCID ProfileGilles Augusto, Adam Berg, View ORCID ProfileLuke Thorley, Rameswara R Segireddy, View ORCID ProfileThomas A Bowden, View ORCID ProfileAlexander D Douglas
doi: https://doi.org/10.1101/2022.02.28.482293
Weng M Ng
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
2Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN
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Sofiya Fedosyuk
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
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Solomon English
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
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Gilles Augusto
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
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Adam Berg
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
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Luke Thorley
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
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Rameswara R Segireddy
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
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Thomas A Bowden
2Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN
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  • For correspondence: sandy.douglas@ndm.ox.ac.uk thomas.bowden@strubi.ox.ac.uk
Alexander D Douglas
1Jenner Institute, Centre for Cellular and Molecular Physiology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN
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  • For correspondence: sandy.douglas@ndm.ox.ac.uk thomas.bowden@strubi.ox.ac.uk
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Summary

Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G’s pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies which can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. We demonstrate that targeted mutations can stabilize RABV-G in the pre-fusion conformation, a key step towards structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and will facilitate the development of improved vaccines and prophylactic antibodies.

Competing Interest Statement

SF and ADD are named inventors on a patent invention relating to stabilization of RABV-G by the H270P mutation.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 28, 2022.
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Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies
Weng M Ng, Sofiya Fedosyuk, Solomon English, Gilles Augusto, Adam Berg, Luke Thorley, Rameswara R Segireddy, Thomas A Bowden, Alexander D Douglas
bioRxiv 2022.02.28.482293; doi: https://doi.org/10.1101/2022.02.28.482293
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Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies
Weng M Ng, Sofiya Fedosyuk, Solomon English, Gilles Augusto, Adam Berg, Luke Thorley, Rameswara R Segireddy, Thomas A Bowden, Alexander D Douglas
bioRxiv 2022.02.28.482293; doi: https://doi.org/10.1101/2022.02.28.482293

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