التفاصيل البيبلوغرافية
| العنوان: |
An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition. |
| المؤلفون: |
Noske, Gabriela Dias, Song, Yun, Fernandes, Rafaela Sachetto, Chalk, Rod, Elmassoudi, Haitem, Koekemoer, Lizbé, Owen, C. David, El-Baba, Tarick J., Robinson, Carol V., The COVID Moonshot Consortium, Oliva, Glaucius, Godoy, Andre Schutzer |
| المصدر: |
Nature Communications; 3/20/2023, Vol. 14 Issue 1, p1-13, 13p |
| مصطلحات موضوعية: |
SARS-CoV-2, MASS spectrometry, DIMERIZATION, VIRAL replication, DIMERS |
| مستخلص: |
The main protease from SARS-CoV-2 (Mpro) is responsible for cleavage of the viral polyprotein. Mpro self-processing is called maturation, and it is crucial for enzyme dimerization and activity. Here we use C145S Mpro to study the structure and dynamics of N-terminal cleavage in solution. Native mass spectroscopy analysis shows that mixed oligomeric states are composed of cleaved and uncleaved particles, indicating that N-terminal processing is not critical for dimerization. A 3.5 Å cryo-EM structure provides details of Mpro N-terminal cleavage outside the constrains of crystal environment. We show that different classes of inhibitors shift the balance between oligomeric states. While non-covalent inhibitor MAT-POS-e194df51-1 prevents dimerization, the covalent inhibitor nirmatrelvir induces the conversion of monomers into dimers, even with intact N-termini. Our data indicates that the Mpro dimerization is triggered by induced fit due to covalent linkage during substrate processing rather than the N-terminal processing. The Main protease of SARS-CoV-2 is key for viral replication, but its maturation process is still not completely understood. Here, the authors not only reveal unique details from the first step of maturation, but also demonstrate how different classes of inhibitor can block this step. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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