Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein.

ABSTRACT: The SARS-CoV-2 papain-like protease (PL^pro) is an antiviral drug target that catalyzes the hydrolysis of the viral polyproteins pp1a/1ab, so releasing the non-structural proteins (nsps) 1-3 that are essential for the coronavirus lifecycle. The LXGG↓X motif in pp1a/1ab is crucial for recognition and cleavage by PL^pro. We describe molecular dynamics, docking, and quantum mechanics/molecular mechanics (QM/MM) calculations to investigate how oligopeptide substrates derived from the viral polyprotein bind to PL^pro. The results reveal how the substrate sequence affects the efficiency of PL^pro-catalyzed hydrolysis. In particular, a proline at the P2' position promotes catalysis, as validated by residue substitutions and mass spectrometry-based analyses.

SUBMITTER: Chan HTH 

PROVIDER: S-EPMC10849127 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature