Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein
The SARS-CoV-2 papain-like protease (PLpro) 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...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Sprog: | English |
| Udgivet: |
Royal Society of Chemistry
2023
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| _version_ | 1826312835875995648 |
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| author | Chan, HTH Brewitz, L Lukacik, P Strain-Damerell, C Walsh, MA Schofield, CJ Duarte, F |
| author_facet | Chan, HTH Brewitz, L Lukacik, P Strain-Damerell, C Walsh, MA Schofield, CJ Duarte, F |
| author_sort | Chan, HTH |
| collection | OXFORD |
| description | The SARS-CoV-2 papain-like protease (PLpro) 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 PLpro. 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 PLpro. The results reveal how the substrate sequence affects the efficiency of PLpro-catalyzed hydrolysis. In particular, a proline at the P2′ position promotes catalysis, as validated by residue substitutions and mass spectrometry-based analyses. Analysis of PLpro 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 PLpro. The results will help in identifying PLpro substrates and guiding inhibitor design. |
| first_indexed | 2024-09-25T04:01:20Z |
| format | Journal article |
| id | oxford-uuid:20463f6e-ed9f-4610-b565-19c1b3b7562c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:01:20Z |
| publishDate | 2023 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:20463f6e-ed9f-4610-b565-19c1b3b7562c2024-05-01T16:22:45ZStudies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyproteinJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:20463f6e-ed9f-4610-b565-19c1b3b7562cEnglishSymplectic ElementsRoyal Society of Chemistry2023Chan, HTHBrewitz, LLukacik, PStrain-Damerell, CWalsh, MASchofield, CJDuarte, FThe SARS-CoV-2 papain-like protease (PLpro) 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 PLpro. 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 PLpro. The results reveal how the substrate sequence affects the efficiency of PLpro-catalyzed hydrolysis. In particular, a proline at the P2′ position promotes catalysis, as validated by residue substitutions and mass spectrometry-based analyses. Analysis of PLpro 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 PLpro. The results will help in identifying PLpro substrates and guiding inhibitor design. |
| spellingShingle | Chan, HTH Brewitz, L Lukacik, P Strain-Damerell, C Walsh, MA Schofield, CJ Duarte, F Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein |
| title | Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein |
| title_full | Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein |
| title_fullStr | Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein |
| title_full_unstemmed | Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein |
| title_short | Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein |
| title_sort | studies on the selectivity of the sars cov 2 papain like protease reveal the importance of the p2 proline of the viral polyprotein |
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