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TitleSARS-CoV-2 polyprotein substrate regulates the stepwise M cleavage reaction.
Journal, issue, pagesJ Biol Chem, Vol. 299, Issue 5, Page 104697, Year 2023
Publish dateApr 10, 2023
AuthorsManju Narwal / Jean-Paul Armache / Thomas J Edwards / Katsuhiko S Murakami /
PubMed AbstractThe processing of the Coronavirus polyproteins pp1a and pp1ab by the main protease M to produce mature proteins is a crucial event in virus replication and a promising target for antiviral drug ...The processing of the Coronavirus polyproteins pp1a and pp1ab by the main protease M to produce mature proteins is a crucial event in virus replication and a promising target for antiviral drug development. M cleaves polyproteins in a defined order, but how M and/or the polyproteins determine the order of cleavage remains enigmatic due to a lack of structural information about polyprotein-bound M. Here, we present the cryo-EM structures of SARS-CoV-2 M in an apo form and in complex with the nsp7-10 region of the pp1a polyprotein. The complex structure shows that M interacts with only the recognition site residues between nsp9 and nsp10, without any association with the rest of the polyprotein. Comparison between the apo form and polyprotein-bound structures of M highlights the flexible nature of the active site region of M, which allows it to accommodate ten recognition sites found in the polyprotein. These observations suggest that the role of M in selecting a preferred cleavage site is limited and underscores the roles of the structure, conformation, and/or dynamics of the polyproteins in determining the sequence of polyprotein cleavage by M.
External linksJ Biol Chem / PubMed:37044215 / PubMed Central
MethodsEM (single particle)
Resolution2.49 - 3.36 Å
Structure data

28162

8eir

EMDB-28162, PDB-8eir:
SARS-CoV-2 polyprotein substrate regulates the stepwise Mpro cleavage reaction
Method: EM (single particle) / Resolution: 2.49 Å

28200

8eke

EMDB-28200, PDB-8eke:
Cryo-EM structure of SARS CoV-2 Mpro WT protease
Method: EM (single particle) / Resolution: 3.36 Å

Source
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN / SARS COV-2 Main protease (Mpro) in complex with the polyprotein substrate / Main protease / Mpro / SARS CoV-2 / polyprotein

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