Abstract
The main protease (M pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. M pro 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 M pro bound to two viral substrate peptides. The structures show how M pro 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 M pro cleavage sites but conserved among homologous junctions in coronaviruses. M pro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1′ or P2′ can enhance catalysis. Visualization of M pro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.
Keywords: Mpro; SARS-CoV-2; protease; virology.
【저자키워드】 SARS-CoV-2, protease, Virology., MPro, 【초록키워드】 COVID-19, coronavirus disease, Structure, Coronaviruses, coronavirus, Virology, peptide, protease, severe acute respiratory syndrome Coronavirus, antiviral drug, Replication, MPro, viral replication, peptides, Visualization, cleavage, Proteases, crystal structure, homologous, parameters, NSP8, Amino acid, structures, amino acid substitutions, Efficiency, crystal structures, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, residue, M pro, cleavage site, substrate, lifecycle, catalysis, viral nonstructural proteins, polyprotein, amino acid substitution, junction, ENhance, conserved, provide, coronavirus, changes in, unique, recognize, catalytic, cleave, the SARS-CoV-2, viral nonstructural protein, 【제목키워드】 Recognition, substrate, the SARS-CoV-2,