Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease,ACS Infectious Diseases

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Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-08-26 , DOI: 10.1021/acsinfecdis.1c00237
Elizabeth A MacDonald ₁ , Gary Frey , Mark N Namchuk , Stephen C Harrison _{1,

2} , Stephen M Hinshaw , Ian W Windsor _{1,

3}

Affiliation

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.

中文翻译：

SARS-CoV-2 主要蛋白酶对不同病毒底物的识别

冠状病毒病 (COVID-19) 的病因严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的主要蛋白酶 (M ^{pro ) 是药物抑制的理想靶点。}M ^pro在冠状病毒中是保守的，与人类蛋白酶不同。病毒复制取决于病毒多蛋白在多个位点的裂解。我们展示了与两种病毒底物肽结合的SARS-CoV-2 M ^pro的晶体结构。这些结构展示了 M ^pro如何识别不同的底物，以及底物调节的细微变化如何驱动催化效率的巨大变化。一种肽构成病毒非结构蛋白 8 和 9 (nsp8/9) 之间的连接，具有 P1' 和 P2' 残基，这些残基在 SARS-CoV-2 M^前裂解位点中是独特的，但在冠状病毒的同源连接中是保守的。M ^pro裂解 nsp8/9 的效率较低，P1' 或 P2' 处的氨基酸取代可以增强催化作用。具有完整底物的 M ^pro的可视化为抗病毒药物设计提供了新的模板，并表明冠状病毒生命周期选择微调的底物依赖性催化参数。

更新日期：2021-09-10

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