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

Patrick Y. A. Reinke, Robin Schubert, Dominik Oberthür, Marina Galchenkova, Aida Rahmani Mashhour, Sebastian Günther, Anaïs Chretien, Adam Round, Brandon Charles Seychell, Brenna Norton-Baker, Chan Kim, Christina Schmidt, Faisal H. M. Koua, Alexandra Tolstikova, Wiebke Ewert, Gisel Esperanza Peña Murillo, Grant Mills, Henry Kirkwood, Hévila Brognaro, Huijong Han, Jayanath Koliyadu, Joachim Schulz, Johan Bielecki, Julia Lieske, Julia Maracke, Juraj Knoska, Kristina Lorenzen, Lea Brings, Marcin Sikorski, Marco Kloos, Mohammad Vakili, Patrik Vagovic, Philipp Middendorf, Raphael Wijn, Richard Bean, Romain Letrun, Seonghyun Han, Sven Falke, Tian Geng, Tokushi Sato, Vasundara Srinivasan, Yoonhee Kim, Oleksandr M. Yefanov, Luca Gelisio, Tobias Beck, Andrew S. Doré, Adrian P. Mancuso, Christian Betzel, Saša Bajt, Lars Redecke, Henry N. Chapman, Alke Meents, Dušan Turk, Winfried Hinrichs and Thomas J. Lane ()
Additional contact information
Patrick Y. A. Reinke: Deutsches Elektronen-Synchrotron DESY
Robin Schubert: European XFEL GmbH
Dominik Oberthür: Deutsches Elektronen-Synchrotron DESY
Marina Galchenkova: Deutsches Elektronen-Synchrotron DESY
Aida Rahmani Mashhour: Deutsches Elektronen-Synchrotron DESY
Sebastian Günther: Deutsches Elektronen-Synchrotron DESY
Anaïs Chretien: European XFEL GmbH
Adam Round: European XFEL GmbH
Brandon Charles Seychell: Universität Hamburg
Brenna Norton-Baker: Max Plank Institute for the Structure and Dynamics of Matter
Chan Kim: European XFEL GmbH
Christina Schmidt: European XFEL GmbH
Faisal H. M. Koua: European XFEL GmbH
Alexandra Tolstikova: Deutsches Elektronen-Synchrotron DESY
Wiebke Ewert: Deutsches Elektronen-Synchrotron DESY
Gisel Esperanza Peña Murillo: Deutsches Elektronen-Synchrotron DESY
Grant Mills: European XFEL GmbH
Henry Kirkwood: European XFEL GmbH
Hévila Brognaro: Universität Hamburg
Huijong Han: European XFEL GmbH
Jayanath Koliyadu: European XFEL GmbH
Joachim Schulz: European XFEL GmbH
Johan Bielecki: European XFEL GmbH
Julia Lieske: Deutsches Elektronen-Synchrotron DESY
Julia Maracke: Deutsches Elektronen-Synchrotron DESY
Juraj Knoska: Deutsches Elektronen-Synchrotron DESY
Kristina Lorenzen: European XFEL GmbH
Lea Brings: European XFEL GmbH
Marcin Sikorski: European XFEL GmbH
Marco Kloos: European XFEL GmbH
Mohammad Vakili: Deutsches Elektronen-Synchrotron DESY
Patrik Vagovic: Deutsches Elektronen-Synchrotron DESY
Philipp Middendorf: Deutsches Elektronen-Synchrotron DESY
Raphael Wijn: European XFEL GmbH
Richard Bean: European XFEL GmbH
Romain Letrun: European XFEL GmbH
Seonghyun Han: European XFEL GmbH
Sven Falke: Deutsches Elektronen-Synchrotron DESY
Tian Geng: Sosei Heptares
Tokushi Sato: European XFEL GmbH
Vasundara Srinivasan: Universität Hamburg
Yoonhee Kim: European XFEL GmbH
Oleksandr M. Yefanov: Deutsches Elektronen-Synchrotron DESY
Luca Gelisio: European XFEL GmbH
Tobias Beck: Universität Hamburg
Andrew S. Doré: Sosei Heptares
Adrian P. Mancuso: European XFEL GmbH
Christian Betzel: Universität Hamburg
Saša Bajt: Deutsches Elektronen-Synchrotron DESY
Lars Redecke: Universität zu Lübeck
Henry N. Chapman: Deutsches Elektronen-Synchrotron DESY
Alke Meents: Deutsches Elektronen-Synchrotron DESY
Dušan Turk: Jamova cesta 39
Winfried Hinrichs: Felix-Hausdorff-Str. 4
Thomas J. Lane: Deutsches Elektronen-Synchrotron DESY

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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 disulfide bond between the active site cysteine, C145, and a distal cysteine, C117. Previous work proposed this disulfide provides the mechanism of protection from irreversible oxidation. Mpro forms an obligate homodimer, and the C117-C145 structure shows disruption of interactions bridging the dimer interface, implying a correlation between oxidation and dimerization. We confirm dimer stability is weakened in solution upon oxidation. Finally, we observe the protein’s crystallization behavior is linked to its redox state. Oxidized Mpro spontaneously forms a distinct, more loosely packed lattice. Seeding with crystals of this lattice yields a structure with an oxidation pattern incorporating one cysteine-lysine-cysteine (SONOS) and two lysine-cysteine (NOS) bridges. These structures further our understanding of the oxidative regulation of Mpro and the crystallization conditions necessary to study this structurally.

Date: 2024
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DOI: 10.1038/s41467-024-48109-3

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