Journal article
Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2
Proceedings of the National Academy of Sciences - PNAS, Vol.119(16), pp.e2117142119-e2117142119
04/19/2022
DOI: 10.1073/pnas.2117142119
PMCID: PMC9172370
PMID: 35380892
Abstract
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key enzyme, which extensively digests CoV replicase polyproteins essential for viral replication and transcription, making it an attractive target for antiviral drug development. However, the molecular mechanism of how Mpro of SARS-CoV-2 digests replicase polyproteins, releasing the nonstructural proteins (nsps), and its substrate specificity remain largely unknown. Here, we determine the high-resolution structures of SARS-CoV-2 Mpro in its resting state, precleavage state, and postcleavage state, constituting a full cycle of substrate cleavage. The structures show the delicate conformational changes that occur during polyprotein processing. Further, we solve the structures of the SARS-CoV-2 Mpro mutant (H41A) in complex with six native cleavage substrates from replicase polyproteins, and demonstrate that SARS-CoV-2 Mpro can recognize sequences as long as 10 residues but only have special selectivity for four subsites. These structural data provide a basis to develop potent new inhibitors against SARS-CoV-2.
Details
- Title: Subtitle
- Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2
- Creators
- Yao Zhao - ShanghaiTech UniversityYan Zhu - ShanghaiTech UniversityXiang Liu - Nankai UniversityZhenming Jin - ShanghaiTech UniversityYinkai Duan - ShanghaiTech UniversityQi Zhang - ShanghaiTech UniversityChengyao Wu - ShanghaiTech UniversityLu Feng - ShanghaiTech UniversityXiaoyu Du - ShanghaiTech UniversityJinyi Zhao - ShanghaiTech UniversityMaolin Shao - ShanghaiTech UniversityBing Zhang - ShanghaiTech UniversityXiuna Yang - ShanghaiTech UniversityLijie Wu - ShanghaiTech UniversityXiaoyun Ji - Nanjing UniversityLuke W Guddat - University of QueenslandKailin Yang - Cleveland ClinicZihe Rao - Tsinghua UniversityHaitao Yang - ShanghaiTech University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.119(16), pp.e2117142119-e2117142119
- DOI
- 10.1073/pnas.2117142119
- PMID
- 35380892
- PMCID
- PMC9172370
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Language
- English
- Date published
- 04/19/2022
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696578602771
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