- By:
- Hameedi, Mikhail; Teixeira Prates, Erica ; Garvin, Michael R; Mathews, Irimpan; Amos, B K; Demerdash, Omar N; Bechthold, Mark; Iyer, Mamta; Rahighi, Simin; Kneller, Daniel W; Irle, Stephan ; Vuong, Van Quan ; Mitchell, Julie C; Labbe, Audrey D; Galanie, Stephanie S; Wakatsuki, Soichi; Jacobson, Daniel A; Kovalevskyi, Andrii Y
- Journal Name:
- Nature Communications
- Page Number:
- 5285
- Volume:
- 13
- Issue Number:
- 1
- Publication Date:
- December 27, 2023
- View DOI Listing:
- https://doi.org/10.1038/s41467-022-32922-9
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 NEMO226–234 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.
