This model shows the interactions between VIR250 and the active site of the SARS-CoV-2 papain-like protease (PLpro), which plays a vital role in viral replication through its production of nsp1, nsp2, and nsp3, as well as dampening the host’s inflammatory and antiviral responses (through hydrolysis of ubiquitin and ISG15, respectively). PLpro recognises the tetrapeptide LXGG-motif found between nsps 1, 2, 3, and 4, as well as between ubiquitin/ISG15 and the ε-amino group of a lysine side chain located on host cell proteins, and its catalytic triad (comprised of Cys-111, His-272, and Asp-286) hydrolyses the peptide bond located on the carboxyl side of glycine at the P1 position. VIR250 forms a covalent thioether linkage with the catalytic cysteine resulting in irreversible inhibition of the enzyme, while Van der Waals interactions, hydrogen bonds, and hydrophobic interactions help position it throughout the S4-S1 pockets of the active site.
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