{"doi":"10.1101/2025.01.28.635221","title":"Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome","abstract":"Abstract The 20S proteasome, a critical component of the ubiquitin-proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), a natural γ-lactam-β-lactone compound derived from Salinispora tropica , is a potent 20S proteasome covalent inhibitor with demonstrated anticancer properties. Its broad-spectrum inhibition of all three proteasome subunits and ability to cross the blood-brain barrier has made it a promising therapeutic candidate for glioblastoma. Here, we present the cryo-EM structure of the human 20S proteasome in complex with MZB at 2.55 Å resolution. This structure reveals the binding mode of MZB to all six catalytic subunits within the two β-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings explain the therapeutic potential of MZB at the molecular level and highlight marine-derived natural products in targeting the proteasome for anticancer treatment.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555379,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":447645,"name":"Pavla Fajtová","orcid":"0000-0002-4029-0706","position":1,"is_corresponding":false},{"id":1454177,"name":"Anthony O Donoghue","orcid":null,"position":2,"is_corresponding":false},{"id":550573,"name":"Evžen Bouřa","orcid":"0000-0002-9652-4065","position":3,"is_corresponding":false},{"id":550571,"name":"Jan Šilhán","orcid":"0000-0003-3868-5714","position":4,"is_corresponding":false},{"id":1293986,"name":"Hagen Sülzen","orcid":"0000-0001-7636-700X","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:54:59.329539Z","pmid":"39974992","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":[]}