tetano
Editor, Senior Moderator
RSC Chem Biol
. 2023 Oct 24;5(2):117-130.
doi: 10.1039/d3cb00128h. eCollection 2024 Feb 7. Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein
H T Henry Chan[SUP] 1 [/SUP], Lennart Brewitz[SUP] 1 [/SUP], Petra Lukacik[SUP] 2 3 [/SUP], Claire Strain-Damerell[SUP] 2 3 [/SUP], Martin A Walsh[SUP] 2 3 [/SUP], Christopher J Schofield[SUP] 1 [/SUP], Fernanda Duarte[SUP] 1 [/SUP]
Affiliations
The SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) 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[SUP]pro[/SUP]. 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[SUP]pro[/SUP]. The results reveal how the substrate sequence affects the efficiency of PL[SUP]pro[/SUP]-catalyzed hydrolysis. In particular, a proline at the P2' position promotes catalysis, as validated by residue substitutions and mass spectrometry-based analyses. Analysis of PL[SUP]pro[/SUP] catalyzed hydrolysis of LXGG motif-containing oligopeptides derived from human proteins suggests that factors beyond the LXGG motif and the presence of a proline residue at P2' contribute to catalytic efficiency, possibly reflecting the promiscuity of PL[SUP]pro[/SUP]. The results will help in identifying PL[SUP]pro[/SUP] substrates and guiding inhibitor design.
. 2023 Oct 24;5(2):117-130.
doi: 10.1039/d3cb00128h. eCollection 2024 Feb 7. Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein
H T Henry Chan[SUP] 1 [/SUP], Lennart Brewitz[SUP] 1 [/SUP], Petra Lukacik[SUP] 2 3 [/SUP], Claire Strain-Damerell[SUP] 2 3 [/SUP], Martin A Walsh[SUP] 2 3 [/SUP], Christopher J Schofield[SUP] 1 [/SUP], Fernanda Duarte[SUP] 1 [/SUP]
Affiliations
- PMID: 38333195
- PMCID: PMC10849127
- DOI: 10.1039/d3cb00128h
The SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) 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[SUP]pro[/SUP]. 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[SUP]pro[/SUP]. The results reveal how the substrate sequence affects the efficiency of PL[SUP]pro[/SUP]-catalyzed hydrolysis. In particular, a proline at the P2' position promotes catalysis, as validated by residue substitutions and mass spectrometry-based analyses. Analysis of PL[SUP]pro[/SUP] catalyzed hydrolysis of LXGG motif-containing oligopeptides derived from human proteins suggests that factors beyond the LXGG motif and the presence of a proline residue at P2' contribute to catalytic efficiency, possibly reflecting the promiscuity of PL[SUP]pro[/SUP]. The results will help in identifying PL[SUP]pro[/SUP] substrates and guiding inhibitor design.