{"doi":"10.1101/2021.07.16.452547","title":"Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma","abstract":"Abstract Proteasome substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru β-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13 Pru ) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13 Pru , causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis and increased p62 levels. These data establish hRpn13 as an anti-cancer target for multiple myeloma and introduce an hRpn13-targeting scaffold that can be optimized for preclinical trials against hRpn13 Pru -producing cancer types.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":219123,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"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":690646,"name":"Venkata R. Sabbasani","orcid":"0000-0002-4558-2812","position":1,"is_corresponding":false},{"id":494929,"name":"Vasty Osei-Amponsa","orcid":null,"position":2,"is_corresponding":false},{"id":312945,"name":"Christine N. Evans","orcid":null,"position":3,"is_corresponding":false},{"id":690647,"name":"Julianna C. King","orcid":"0000-0001-8968-5664","position":4,"is_corresponding":false},{"id":325214,"name":"Sergey G. Tarasov","orcid":"0000-0002-7134-0374","position":5,"is_corresponding":false},{"id":511860,"name":"Marzena Dyba","orcid":null,"position":6,"is_corresponding":false},{"id":519463,"name":"King C. Chan","orcid":"0000-0002-5355-3501","position":7,"is_corresponding":false},{"id":298285,"name":"Charles D. Schwieters","orcid":"0000-0002-4216-4658","position":8,"is_corresponding":false},{"id":691540,"name":"Sulbha Choudhari","orcid":null,"position":9,"is_corresponding":false},{"id":690648,"name":"Caroline Fromont","orcid":"0000-0003-0844-9980","position":10,"is_corresponding":false},{"id":228426,"name":"Yongmei Zhao","orcid":"0000-0003-0800-4658","position":11,"is_corresponding":false},{"id":271310,"name":"Bao Tran","orcid":"0000-0002-0261-4458","position":12,"is_corresponding":false},{"id":316960,"name":"Xiang Chen","orcid":"0000-0002-0036-0212","position":13,"is_corresponding":false},{"id":438121,"name":"Hiroshi Matsuo","orcid":"0000-0002-4559-6157","position":14,"is_corresponding":false},{"id":276014,"name":"Þorkell Andrésson","orcid":"0000-0002-9545-2450","position":15,"is_corresponding":false},{"id":260578,"name":"Raj Chari","orcid":"0000-0002-2216-313X","position":16,"is_corresponding":false},{"id":663568,"name":"Rolf E. Swenson","orcid":"0000-0001-7804-7202","position":17,"is_corresponding":false},{"id":325215,"name":"Nadya I. Tarasova","orcid":"0000-0002-4949-0069","position":18,"is_corresponding":false},{"id":316963,"name":"Kylie J. Walters","orcid":"0000-0001-7590-2891","position":19,"is_corresponding":false},{"id":475409,"name":"Xiuxiu Lu","orcid":"0000-0002-9591-7334","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:33.915158Z","pmid":null,"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":[]}