Updated models of (A) ISG15 (yellow) and (B) K48-Ub₂ (orange) and bound to PLpro (blue).

<p>The ubiquitin hydrophobic patch residues are shown in magenta. PLpro residues identified through site-directed mutagenesis as important for K48-Ub₂ and ISG15 binding are highlighted in a yellow circle. The two distal regions involved in binding Ub2 or ISG15 are labeled as distal-1 (closest to active site, location of single ubiquitin binding) and distal-2 (binding of second ubiquitin-like domain).