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@ARTICLE{Reinke:593910,
author = {Reinke, Patrick and Schubert, Robin and Oberthür, Dominik
and Galchenkova, Marina and Rahmani Mashhour, Aida and
Guenther, Sebastian and Chretien, Anaïs and Round, Adam and
Seychell, Brandon Charles and Norton-Baker, Brenna and Kim,
Chan and Schmidt, Christina and Koua, Faisal H. M. and
Tolstikova, Alexandra and Ewert, Wiebke and Pena Murillo,
Gisel Esperanza and Mills, Grant and Kirkwood, Henry and
Brognaro, Hévila and Han, Huijong and Koliyadu, Jayanath
and Schulz, Joachim and Bielecki, Johan and Lieske, Julia
and Maracke, Julia and Knoska, Juraj and Lorenzen, Kristina
and Brings, Lea and Sikorski, Marcin and Kloos, Marco and
Vakili, Mohammad and Vagovic, Patrik and Middendorf, Philipp
and de Wijn, Raphael and Bean, Richard and Letrun, Romain
and Han, Seonghyun and Falke, Sven and Geng, Tian and Sato,
Tokushi and Srinivasan, Vasundara and Kim, Yoonhee and
Yefanov, Oleksandr M. and Gelisio, Luca and Beck, Tobias and
Doré, Andrew S. and Mancuso, Adrian P. and Betzel,
Christian and Bajt, Saša and Redecke, Lars and Chapman,
Henry N. and Meents, Alke and Turk, Dušan and Hinrichs,
Winfried and Lane, Thomas},
title = {{SARS}-{C}o{V}-2 {M}pro responds to oxidation by forming
disulfide and {NOS}/{SONOS} bonds},
journal = {Nature Communications},
volume = {15},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {PUBDB-2023-05575},
pages = {3827},
year = {2024},
abstract = {The main protease (M$^{pro}$) 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 M$^{pro}$ 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. M$^{pro}$ 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 M$^{pro}$
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 M$^{pro}$ and the
crystallization conditions necessary to study this
structurally.},
cin = {CFEL-I / FS-CFEL-1-PBIO / FS-CFEL-1-BMX /
$XFEL_E1_SPB/SFX$},
ddc = {500},
cid = {I:(DE-H253)CFEL-I-20161114 /
I:(DE-H253)FS-CFEL-1-PBIO-20210408 /
I:(DE-H253)FS-CFEL-1-BMX-20210408 /
$I:(DE-H253)XFEL_E1_SPB_SFX-20210408$},
pnm = {633 - Life Sciences – Building Blocks of Life: Structure
and Function (POF4-633) / 6G3 - PETRA III (DESY) (POF4-6G3)
/ InternLabs-0011 - HIR3X - Helmholtz International
Laboratory on Reliability, Repetition, Results at the most
advanced X-ray Sources $(2020_InternLabs-0011)$ / FISCOV -
FISCOV Helmholtz large research infrastructures in the fight
against epidemic outbreaks (FISCOV) / DFG project
G:(GEPRIS)390715994 - EXC 2056: CUI: Advanced Imaging of
Matter (390715994) / DFG project G:(GEPRIS)194651731 - EXC
1074: Hamburger Zentrum für ultraschnelle Beobachtung
(CUI): Struktur, Dynamik und Kontrolle von Materie auf
atomarer Skala (194651731)},
pid = {G:(DE-HGF)POF4-633 / G:(DE-HGF)POF4-6G3 /
$G:(DE-HGF)2020_InternLabs-0011$ / G:(DE-HGF)FISCOV /
G:(GEPRIS)390715994 / G:(GEPRIS)194651731},
experiment = {EXP:(DE-H253)P-P11-20150101 /
EXP:(DE-H253)XFEL-SPB-20150101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38714735},
UT = {WOS:001215774800049},
doi = {10.1038/s41467-024-48109-3},
url = {https://bib-pubdb1.desy.de/record/593910},
}