The H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease
© 2023. Springer Nature Limited..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 12. Sept., Seite 5625 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tran, Norman [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.09.2023 Date Revised 12.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-40023-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM361972695 |
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| 245 | 1 | 4 | |a The H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease |
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| 520 | |a © 2023. Springer Nature Limited. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Dasari, Sathish |e verfasserin |4 aut | |
| 700 | 1 | |a Barwell, Sarah A E |e verfasserin |4 aut | |
| 700 | 1 | |a McLeod, Matthew J |e verfasserin |4 aut | |
| 700 | 1 | |a Kalyaanamoorthy, Subha |e verfasserin |4 aut | |
| 700 | 1 | |a Holyoak, Todd |e verfasserin |4 aut | |
| 700 | 1 | |a Ganesan, Aravindhan |e verfasserin |4 aut | |
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