{"doi":"10.1016/j.celrep.2021.109754","title":"A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease","abstract":"The SARS-CoV-2 papain-like protease (PLpro) is a target for antiviral drug development. It is essential for processing viral polyproteins for replication and functions in host immune evasion by cleaving ubiquitin (Ub) and ubiquitin-like protein (Ubl) conjugates. While highly conserved, SARS-CoV-2 and SARS-CoV PLpro have contrasting Ub/Ubl substrate preferences. Using a combination of structural analyses and functional assays, we identify a molecular sensor within the S1 Ub-binding site of PLpro that serves as a key determinant of substrate specificity. Variations within the S1 sensor specifically alter cleavage of Ub substrates but not of the Ubl interferon-stimulated gene 15 protein (ISG15). Significantly, a variant of concern associated with immune evasion carries a mutation in the S1 sensor that enhances PLpro activity on Ub substrates. Collectively, our data identify the S1 sensor region as a potential hotspot of variability that could alter host antiviral immune responses to newly emerging SARS-CoV-2 lineages.","journal":"Cell Reports","year":2021,"id":156803,"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":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9622,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227430,"name":"Zongyang Lv","orcid":"0000-0002-8862-113X","position":1,"is_corresponding":false},{"id":227429,"name":"Wioletta Rut","orcid":"0000-0003-1261-5566","position":2,"is_corresponding":false},{"id":227435,"name":"Miklós Békés","orcid":"0000-0001-8423-9235","position":3,"is_corresponding":false},{"id":227436,"name":"Marcin Drąg","orcid":"0000-0001-8510-1967","position":4,"is_corresponding":false},{"id":227437,"name":"Shaun K. Olsen","orcid":"0000-0002-1265-7101","position":5,"is_corresponding":false},{"id":227434,"name":"Tony T. Huang","orcid":"0000-0001-9291-5002","position":6,"is_corresponding":false},{"id":229651,"name":"Stephanie Patchett","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:44:13.017332Z","pmid":"34547223","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":[]}