{"doi":"10.1016/j.jbc.2023.104697","title":"SARS-CoV-2 polyprotein substrate regulates the stepwise Mpro cleavage reaction","abstract":"The processing of the Coronavirus polyproteins pp1a and pp1ab by the main protease M pro to produce mature proteins is a crucial event in virus replication and a promising target for antiviral drug development. M pro cleaves polyproteins in a defined order, but how M pro and/or the polyproteins determine the order of cleavage remains enigmatic due to a lack of structural information about polyprotein-bound M pro . Here, we present the cryo-EM structures of SARS-CoV-2 M pro in an apo form and in complex with the nsp7-10 region of the pp1a polyprotein. The complex structure shows that M pro 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 pro highlights the flexible nature of the active site region of M pro , which allows it to accommodate ten recognition sites found in the polyprotein. These observations suggest that the role of M pro 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 pro .","journal":"Journal of Biological Chemistry","year":2023,"id":324261,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":98191,"name":"Jean‐Paul Armache","orcid":"0000-0001-9195-2282","position":1,"is_corresponding":false},{"id":531825,"name":"Thomas J. Edwards","orcid":"0000-0003-2561-6728","position":2,"is_corresponding":false},{"id":415430,"name":"Katsuhiko Murakami","orcid":"0000-0003-2244-0501","position":3,"is_corresponding":false},{"id":842105,"name":"M. Narwal","orcid":"0000-0002-9718-5827","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-19T01:08:11.275604Z","pmid":"37044215","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}