A model of SARS-CoV-2 papain-like protease (PlPro) and some of its interactions with the VIR250 inhibitor. The site on the enzyme we’re interested in is white, the inhibitor is in green and the hydrogen bonds are represented as dotted lines. PlPro cleaves recognisable sites between other non-structural viral proteins: nsp1/2, 2/3 and 3/4 releasing the first three into the host cell which play a role in the virus’ replication. It also removes ubiquitins. cleaving the chains effectively bypasses some immune responses as these are often markers on deficient proteins for proteolysis also known as a cell’s recycling (must make it easier even to hide as the cell is busy dealing with the extra ‘rubbish). Once VIR250 binds to PlPro, the enzyme’s shape changes and the thioether bond prevents it from binding to its ‘normal’ targets (notably Lys48 of the ubiquitin chain sequence) redering it ‘useless’. VIR250 may however also inhibit some of the host’s own proteases.
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