Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape.

ABSTRACT: Papain-like protease (PLpro) is an attractive drug target for SARS-CoV-2 because it is essential for viral replication, cleaving viral poly-proteins pp1a and pp1ab, and has de-ubiquitylation and de-ISGylation activities, affecting innate immune responses. We employ Deep Mutational Scanning to evaluate the mutational effects on PLpro enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify mutations in neighboring residues that alter activity. We characterize residues responsible for substrate binding and demonstrate that although residues in the blocking loop are remarkably tolerant to mutation, blocking loop flexibility is important for function. We additionally find a connected network of mutations affecting activity that extends fa

SUBMITTER: Wu X 

PROVIDER: S-EPMC11266423 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature