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Lu, Xiuxiu; Sabbasani, Venkata R; Osei-Amponsa, Vasty; Evans, Christine N; King, Julianna C; Tarasov, Sergey G; Dyba, Marzena; Das, Sudipto; Chan, King C; Schwieters, Charles D; Choudhari, Sulbha; Fromont, Caroline; Zhao, Yongmei; Tran, Bao; Chen, Xiang; Matsuo, Hiroshi; Andresson, Thorkell; Chari, Raj; Swenson, Rolf E; Tarasova, Nadya I; Walters, Kylie J
Nature communications, 12/2021, Letnik: 12, Številka: 1Journal Article
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 ) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13 , causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis. 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 -producing cancer types.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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