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Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma.
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.
Afiliação
  • Lu X; Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • Sabbasani VR; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Osei-Amponsa V; Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • Evans CN; Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
  • King JC; Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
  • Tarasov SG; Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • Dyba M; Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • Das S; Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, 21702, USA.
  • Chan KC; Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, 21702, USA.
  • Schwieters CD; Computational Biomolecular Magnetic Resonance Core, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-5620, USA.
  • Choudhari S; Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.
  • Fromont C; Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.
  • Zhao Y; Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.
  • Tran B; Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.
  • Chen X; Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • Matsuo H; Basic Science Program, Center for Structural Biology, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
  • Andresson T; Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, 21702, USA.
  • Chari R; Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
  • Swenson RE; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Tarasova NI; Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • Walters KJ; Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA. kylie.walters@nih.gov.
Nat Commun ; 12(1): 7318, 2021 12 16.
Article em En | MEDLINE | ID: mdl-34916494
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 ß-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13Pru) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13Pru, 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 hRpn13Pru-producing cancer types.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos e Proteínas de Sinalização Intracelular / Ubiquitinação / Mieloma Múltiplo Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos e Proteínas de Sinalização Intracelular / Ubiquitinação / Mieloma Múltiplo Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article