IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40023-4.html
   My bibliography  Save this article

The H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease

Author

Listed:
  • Norman Tran

    (University of Waterloo)

  • Sathish Dasari

    (University of Waterloo)

  • Sarah A. E. Barwell

    (University of Waterloo)

  • Matthew J. McLeod

    (Cornell University)

  • Subha Kalyaanamoorthy

    (University of Waterloo)

  • Todd Holyoak

    (University of Waterloo)

  • Aravindhan Ganesan

    (University of Waterloo)

Abstract

The main protease of SARS-CoV-2 (Mpro) is an important target for developing COVID-19 therapeutics. Recent work has highlighted Mpro’s susceptibility to undergo redox-associated conformational changes in response to cellular and immune-system-induced oxidation. Despite structural evidence indicating large-scale rearrangements upon oxidation, the mechanisms of conformational change and its functional consequences are poorly understood. Here, we present the crystal structure of an Mpro point mutant (H163A) that shows an oxidized conformation with the catalytic cysteine in a disulfide bond. We hypothesize that Mpro adopts this conformation under oxidative stress to protect against over-oxidation. Our metadynamics simulations illustrate a potential mechanism by which H163 modulates this transition and suggest that this equilibrium exists in the wild type enzyme. We show that other point mutations also significantly shift the equilibrium towards this state by altering conformational free energies. Unique avenues of SARS-CoV-2 research can be explored by understanding how H163 modulates this equilibrium.

Suggested Citation

  • Norman Tran & Sathish Dasari & Sarah A. E. Barwell & Matthew J. McLeod & Subha Kalyaanamoorthy & Todd Holyoak & Aravindhan Ganesan, 2023. "The H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40023-4
    DOI: 10.1038/s41467-023-40023-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40023-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-40023-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jaeyong Lee & Liam J. Worrall & Marija Vuckovic & Federico I. Rosell & Francesco Gentile & Anh-Tien Ton & Nathanael A. Caveney & Fuqiang Ban & Artem Cherkasov & Mark Paetzel & Natalie C. J. Strynadka, 2020. "Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    2. Marie Wensien & Fabian Rabe Pappenheim & Lisa-Marie Funk & Patrick Kloskowski & Ute Curth & Ulf Diederichsen & Jon Uranga & Jin Ye & Pan Fang & Kuan-Ting Pan & Henning Urlaub & Ricardo A. Mata & Vikto, 2021. "A lysine–cysteine redox switch with an NOS bridge regulates enzyme function," Nature, Nature, vol. 593(7859), pages 460-464, May.
    3. Zhenming Jin & Xiaoyu Du & Yechun Xu & Yongqiang Deng & Meiqin Liu & Yao Zhao & Bing Zhang & Xiaofeng Li & Leike Zhang & Chao Peng & Yinkai Duan & Jing Yu & Lin Wang & Kailin Yang & Fengjiang Liu & Re, 2020. "Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors," Nature, Nature, vol. 582(7811), pages 289-293, June.
    4. Wayne Vuong & Muhammad Bashir Khan & Conrad Fischer & Elena Arutyunova & Tess Lamer & Justin Shields & Holly A. Saffran & Ryan T. McKay & Marco J. Belkum & Michael A. Joyce & Howard S. Young & D. Lorn, 2020. "Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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, 2024. "SARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jaeyong Lee & Calem Kenward & Liam J. Worrall & Marija Vuckovic & Francesco Gentile & Anh-Tien Ton & Myles Ng & Artem Cherkasov & Natalie C. J. Strynadka & Mark Paetzel, 2022. "X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Lisa-Marie Funk & Gereon Poschmann & Fabian Rabe von Pappenheim & Ashwin Chari & Kim M. Stegmann & Antje Dickmanns & Marie Wensien & Nora Eulig & Elham Paknia & Gabi Heyne & Elke Penka & Arwen R. Pear, 2024. "Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Hengrui Liu & Sho Iketani & Arie Zask & Nisha Khanizeman & Eva Bednarova & Farhad Forouhar & Brandon Fowler & Seo Jung Hong & Hiroshi Mohri & Manoj S. Nair & Yaoxing Huang & Nicholas E. S. Tay & Sumin, 2022. "Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Rana Abdelnabi & Dirk Jochmans & Kim Donckers & Bettina Trüeb & Nadine Ebert & Birgit Weynand & Volker Thiel & Johan Neyts, 2023. "Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in female Syrian hamsters and retains partial susceptibility to treatment," Nature Communications, Nature, vol. 14(1), pages 1-7, December.
    5. Nik Franko & Ana Palma Teixeira & Shuai Xue & Ghislaine Charpin-El Hamri & Martin Fussenegger, 2021. "Design of modular autoproteolytic gene switches responsive to anti-coronavirus drug candidates," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    6. Gabriela Dias Noske & Yun Song & Rafaela Sachetto Fernandes & Rod Chalk & Haitem Elmassoudi & Lizbé Koekemoer & C. David Owen & Tarick J. El-Baba & Carol V. Robinson & Glaucius Oliva & Andre Schutzer , 2023. "An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Mohammad (Behdad) Jamshidi & Omid Moztarzadeh & Alireza Jamshidi & Ahmed Abdelgawad & Ayman S. El-Baz & Lukas Hauer, 2023. "Future of Drug Discovery: The Synergy of Edge Computing, Internet of Medical Things, and Deep Learning," Future Internet, MDPI, vol. 15(4), pages 1-15, April.
    8. Ala M. Shaqra & Sarah N. Zvornicanin & Qiu Yu J. Huang & Gordon J. Lockbaum & Mark Knapp & Laura Tandeske & David T. Bakan & Julia Flynn & Daniel N. A. Bolon & Stephanie Moquin & Dustin Dovala & Nese , 2022. "Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    9. Yida Jiang & Xinghe Zhang & Honggang Nie & Jianxiong Fan & Shuangshuang Di & Hui Fu & Xiu Zhang & Lijuan Wang & Chun Tang, 2024. "Dissecting diazirine photo-reaction mechanism for protein residue-specific cross-linking and distance mapping," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    10. Zeyin Yan & Dacong Wei & Xin Li & Lung Wa Chung, 2024. "Accelerating reliable multiscale quantum refinement of protein–drug systems enabled by machine learning," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    11. Michael H. J. Rhodin & Archie C. Reyes & Anand Balakrishnan & Nalini Bisht & Nicole M. Kelly & Joyce Sweeney Gibbons & Jonathan Lloyd & Michael Vaine & Tessa Cressey & Miranda Crepeau & Ruichao Shen &, 2024. "The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    12. Xiangrui Jiang & Haixia Su & Weijuan Shang & Feng Zhou & Yan Zhang & Wenfeng Zhao & Qiumeng Zhang & Hang Xie & Lei Jiang & Tianqing Nie & Feipu Yang & Muya Xiong & Xiaoxing Huang & Minjun Li & Ping Ch, 2023. "Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    13. Yung-Lin Wang & Chin-Yuan Chang & Ning-Shian Hsu & I-Wen Lo & Kuan-Hung Lin & Chun-Liang Chen & Chi-Fon Chang & Zhe-Chong Wang & Yasushi Ogasawara & Tohru Dairi & Chitose Maruyama & Yoshimitsu Hamano , 2023. "N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    14. Ella Borberg & Eran Granot & Fernando Patolsky, 2022. "Ultrafast one-minute electronic detection of SARS-CoV-2 infection by 3CLpro enzymatic activity in untreated saliva samples," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    15. Tetsuro Matsunaga & Hirohito Sano & Katsuya Takita & Masanobu Morita & Shun Yamanaka & Tomohiro Ichikawa & Tadahisa Numakura & Tomoaki Ida & Minkyung Jung & Seiryo Ogata & Sunghyeon Yoon & Naoya Fujin, 2023. "Supersulphides provide airway protection in viral and chronic lung diseases," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    16. Federico Iacovelli & Gaetana Costanza & Alice Romeo & Terenzio Cosio & Caterina Lanna & Antonino Bagnulo & Umberto Di Maio & Alice Sbardella & Roberta Gaziano & Sandro Grelli & Ettore Squillaci & Ales, 2022. "Interaction of Pelargonium sidoides Compounds with Lactoferrin and SARS-CoV-2: Insights from Molecular Simulations," IJERPH, MDPI, vol. 19(9), pages 1-22, April.
    17. Mikhail A. Hameedi & Erica T. Prates & Michael R. Garvin & Irimpan I. Mathews & B. Kirtley Amos & Omar Demerdash & Mark Bechthold & Mamta Iyer & Simin Rahighi & Daniel W. Kneller & Andrey Kovalevsky &, 2022. "Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    18. Rana Abdelnabi & Caroline S. Foo & Dirk Jochmans & Laura Vangeel & Steven De Jonghe & Patrick Augustijns & Raf Mols & Birgit Weynand & Thanaporn Wattanakul & Richard M. Hoglund & Joel Tarning & Charle, 2022. "The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    19. Filip Mihalič & Caroline Benz & Eszter Kassa & Richard Lindqvist & Leandro Simonetti & Raviteja Inturi & Hanna Aronsson & Eva Andersson & Celestine N. Chi & Norman E. Davey & Anna K. Överby & Per Jemt, 2023. "Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    20. Dongtak Lee & Hyo Gi Jung & Dongsung Park & Junho Bang & Da Yeon Cheong & Jae Won Jang & Yonghwan Kim & Seungmin Lee & Sang Won Lee & Gyudo Lee & Yeon Ho Kim & Ji Hye Hong & Kyo Seon Hwang & Jeong Hoo, 2024. "Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40023-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.