{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lu X"],"funding":["Intramural NIH HHS","U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute"],"pagination":["7318"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8677766"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["12(1)"],"pubmed_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<sup>Pru</sup>) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13<sup>Pru</sup>, ca"],"journal":["Nature communications"],"pubmed_title":["Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma."],"pmcid":["PMC8677766"],"funding_grant_id":["ZIA BC011490","ZIA BC011627","1 ZIA BC011490","1 ZIA BC011627"],"pubmed_authors":["Chari R","Dyba M","Matsuo H","Andresson T","Swenson RE","Walters KJ","Osei-Amponsa V","Chan KC","Lu X","Das S","Choudhari S","Tran B","Fromont C","Zhao Y","Evans CN","Tarasov SG","Sabbasani VR","Tarasova NI","Chen X","Schwieters CD","King JC"],"additional_accession":[]},"is_claimable":false,"name":"Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma.","description":"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<sup>Pru</sup>) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13<sup>Pru</sup>, ca","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Dec","modification":"2026-05-09T01:27:52.315Z","creation":"2022-02-11T14:48:19.637Z"},"accession":"S-EPMC8677766","cross_references":{"pubmed":["34916494"],"doi":["10.1038/s41467-021-27570-4"]}}