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DOE OSTI · 1886096

Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro

Hameedi, Mikhail A.·T. Prates, Erica (ORCID:0000000265815054)·Garvin, Michael R.·Mathews, Irimpan I. (ORCID:0000000162543519)·Amos, B. Kirtley (ORCID:0000000321522927)·Demerdash, Omar·Bechthold, Mark·Iyer, Mamta·Rahighi, Simin·Kneller, Daniel W. (ORCID:0000000254165789)·Kovalevsky, Andrey (ORCID:0000000344599142)·Irle, Stephan (ORCID:0000000349954991)·Vuong, Van-Quan (ORCID:0000000185808532)·Mitchell, Julie C. (ORCID:0000000250317343)·Labbe, Audrey·Galanie, Stephanie·Wakatsuki, Soichi (ORCID:0000000158967968)·Jacobson, Daniel (ORCID:0000000298228251)
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Abstract

Abstract In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like protease (3CLpro) can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.50 Å resolution crystal structure of 3CLpro C145S bound to NEMO 226–234 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro-NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for, in the pathology of COVID-19.

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60 APPLIED LIFE SCIENCES

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Hameedi, Mikhail A., T. Prates, Erica (ORCID:0000000265815054), Garvin, Michael R., Mathews, Irimpan I. (ORCID:0000000162543519), Amos, B. Kirtley (ORCID:0000000321522927), Demerdash, Omar, Bechthold, Mark, Iyer, Mamta, Rahighi, Simin, Kneller, Daniel W. (ORCID:0000000254165789), Kovalevsky, Andrey (ORCID:0000000344599142), Irle, Stephan (ORCID:0000000349954991), Vuong, Van-Quan (ORCID:0000000185808532), Mitchell, Julie C. (ORCID:0000000250317343), Labbe, Audrey, Galanie, Stephanie, Wakatsuki, Soichi (ORCID:0000000158967968), Jacobson, Daniel (ORCID:0000000298228251). 2022-09-08. Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro. https://doi.org/10.1038/s41467-022-32922-9

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