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Nat Commun2024;15(1):3827.May 7, 2024Journal Article

SARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds.

Patrick Y A Reinke1, Robin Schubert2, Dominik Oberthür1, Marina Galchenkova1, Aida Rahmani Mashhour1, Sebastian Günther1, Anaïs Chretien2, Adam Round2, Brandon Charles Seychell3, Brenna Norton-Baker4,5, Chan Kim2, Christina Schmidt2, Faisal H M Koua2, Alexandra Tolstikova1, Wiebke Ewert1, Gisel Esperanza Peña Murillo1,6, Grant Mills2, Henry Kirkwood2, Hévila Brognaro7, Huijong Han2, Jayanath Koliyadu2, Joachim Schulz2, Johan Bielecki2, Julia Lieske1, Julia Maracke1, Juraj Knoska1,6, Kristina Lorenzen2, Lea Brings2, Marcin Sikorski2, Marco Kloos2, Mohammad Vakili1,2, Patrik Vagovic1,2, Philipp Middendorf1, Raphael de Wijn2, Richard Bean2, Romain Letrun2, Seonghyun Han2,8, Sven Falke1, Tian Geng9, Tokushi Sato2, Vasundara Srinivasan7, Yoonhee Kim2, Oleksandr M Yefanov1, Luca Gelisio2, Tobias Beck3,10, Andrew S Doré9,11, Adrian P Mancuso2,12,13, Christian Betzel7,10, Saša Bajt1,10, Lars Redecke14,15, Henry N Chapman1,6,10, Alke Meents1, Dušan Turk16,17, Winfried Hinrichs18, Thomas J Lane19,20,21
1Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607, Hamburg, Germany.
2European XFEL GmbH, Holzkoppel 4, 22869, Schenefeld, Germany.
3Institute of Physical Chemistry, Department of Chemistry, Universität Hamburg, Grindelallee 117, 20146, Hamburg, Germany.
4Max Plank Institute for the Structure and Dynamics of Matter, Luruper Chaussee 149, 22761, Hamburg, Germany.
5Department of Chemistry, University of California at Irvine, Irvine, CA, 92697-2025, USA.
6Department of Physics, Universität Hamburg, Luruper Chaussee 149, 22761, Hamburg, Germany.
7Institute of Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, Universität Hamburg, Build. 22a, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany.
8Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea.
9Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, CB21 6DG, Cambridge, UK.
10The Hamburg Centre for Ultrafast Imaging, Luruper Chaussee 149, 22761, Hamburg, Germany.
11CHARM Therapeutics Ltd., B900 Babraham Research Campus, CB22 3AT, Cambridge, UK.
12La Trobe Institute for Molecular Science, Department of Chemistry and Physics, La Trobe University, Melbourne, VIC, 3086, Australia.
13Diamond Light Source, Harwell Science and Innovation Campus, OX11 0DE, Didcot, UK.
14Institute of Biochemistry, Universität zu Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.
15Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607, Hamburg, Germany.
16Jožef Stefan Institute, Jamova cesta 39, 1000, Ljubljana, Slovenia.
17Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins Jamova 39, 1000, Ljubljana, Slovenia.
18Universität Greifswald, Institute of Biochemistry, Felix-Hausdorff-Str. 4, 17489, Greifswald, Germany.
19Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607, Hamburg, Germany. thomas.lane@desy.de.
20The Hamburg Centre for Ultrafast Imaging, Luruper Chaussee 149, 22761, Hamburg, Germany. thomas.lane@desy.de.
21CHARM Therapeutics Ltd., B900 Babraham Research Campus, CB22 3AT, Cambridge, UK. thomas.lane@desy.de.
PubMed PMC DOI PDF

Abstract

The main protease (Mpro) of SARS-CoV-2 is critical for viral function and a key drug target. Mpro is only active when reduced; turnover ceases upon oxidation but is restored by re-reduction. This suggests the system has evolved to survive periods in an oxidative environment, but the mechanism of this protection has not been confirmed. Here, we report a crystal structure of oxidized Mpro showing a…

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