Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. Mpro is conserved among coronaviruses and distinct from human proteases. Viral replication depends on the cleavage of the viral polyprotein at multiple sites. We present crystal structures of SARS-CoV-2 Mpro bound to two viral substrate peptides. The structures show how Mpro recognizes distinct substrates and how subtle changes in substrate accommodation can drive large changes in catalytic efficiency. One peptide, constituting the junction between viral nonstructural proteins 8 and 9 (nsp8/9), has P1' and P2' residues that are unique among the SARS-CoV-2 Mpro cleavage sites but conserved among homologous junctions in coronaviruses. Mpro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1' or P2' can enhance catalysis. Visualization of Mpro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
ACS infectious diseases - 7(2021), 9 vom: 10. Sept., Seite 2591-2595 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
MacDonald, Elizabeth A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.09.2021 Date Revised 23.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acsinfecdis.1c00237 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM329807250 |
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| 245 | 1 | 0 | |a Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease |
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| 500 | |a Date Completed 14.09.2021 | ||
| 500 | |a Date Revised 23.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. Mpro is conserved among coronaviruses and distinct from human proteases. Viral replication depends on the cleavage of the viral polyprotein at multiple sites. We present crystal structures of SARS-CoV-2 Mpro bound to two viral substrate peptides. The structures show how Mpro recognizes distinct substrates and how subtle changes in substrate accommodation can drive large changes in catalytic efficiency. One peptide, constituting the junction between viral nonstructural proteins 8 and 9 (nsp8/9), has P1' and P2' residues that are unique among the SARS-CoV-2 Mpro cleavage sites but conserved among homologous junctions in coronaviruses. Mpro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1' or P2' can enhance catalysis. Visualization of Mpro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Mpro | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a protease | |
| 650 | 4 | |a virology | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Viral Nonstructural Proteins |2 NLM | |
| 650 | 7 | |a Peptide Hydrolases |2 NLM | |
| 650 | 7 | |a EC 3.4.- |2 NLM | |
| 650 | 7 | |a 3C-like proteinase, SARS-CoV-2 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Coronavirus 3C Proteases |2 NLM | |
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| 700 | 1 | |a Frey, Gary |e verfasserin |4 aut | |
| 700 | 1 | |a Namchuk, Mark N |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, Stephen C |e verfasserin |4 aut | |
| 700 | 1 | |a Hinshaw, Stephen M |e verfasserin |4 aut | |
| 700 | 1 | |a Windsor, Ian W |e verfasserin |4 aut | |
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