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.
【초록키워드】 COVID-19, SARS-CoV-2, pathology, Variation, Proteins, 3CLpro, protease, immune, In vitro assay, specificity, Host immune response, humans, cleavage, information, predict, binding, NF-κB, Signaling, Hydrogen bond, Efficiency, NEMO, residue, help, computational method, hydrophobic, substrate, modulator, machine, polyprotein, Host, addition, accounted, in viral, reveal, explain, cleave, Essential, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, 3CLpro, cleavage, NEMO, functional,