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A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins.
Lu, Xiuxiu; Chandravanshi, Monika; Sabbasani, Venkata R; Gaikwad, Snehal; Hughitt, V Keith; Gyabaah-Kessie, Nana; Scroggins, Bradley T; Das, Sudipto; Myint, Wazo; Clapp, Michelle E; Schwieters, Charles D; Dyba, Marzena A; Bolhuis, Derek L; Koscielniak, Janusz W; Andresson, Thorkell; Emanuele, Michael J; Brown, Nicholas G; Matsuo, Hiroshi; Chari, Raj; Citrin, Deborah E; Mock, Beverly A; Swenson, Rolf E; Walters, Kylie J.
Affiliation
  • Lu X; Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Chandravanshi M; Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Sabbasani VR; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Gaikwad S; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Hughitt VK; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Gyabaah-Kessie N; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Scroggins BT; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Das S; Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
  • Myint W; Cancer Innovation Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Clapp ME; Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, 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, USA.
  • Dyba MA; Biophysics Resource, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Bolhuis DL; Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Koscielniak JW; Basic Science Program, Leidos Biomedical Research Inc., NMR Facility for Biological Research, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Andresson T; Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
  • Emanuele MJ; Department of Pharmacology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Brown NG; Department of Pharmacology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Matsuo H; Cancer Innovation Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Chari R; Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Citrin DE; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Mock BA; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Swenson RE; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Walters KJ; Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. kylie.walters@nih.gov.
Nat Commun ; 15(1): 2485, 2024 Mar 20.
Article in En | MEDLINE | ID: mdl-38509117
ABSTRACT
Proteasome subunit hRpn13 is partially proteolyzed in certain cancer cell types to generate hRpn13Pru by degradation of its UCHL5/Uch37-binding DEUBAD domain and retention of an intact proteasome- and ubiquitin-binding Pru domain. By using structure-guided virtual screening, we identify an hRpn13 binder (XL44) and solve its structure ligated to hRpn13 Pru by integrated X-ray crystallography and NMR to reveal its targeting mechanism. Surprisingly, hRpn13Pru is depleted in myeloma cells following treatment with XL44. TMT-MS experiments reveal a select group of off-targets, including PCNA clamp-associated factor PCLAF and ribonucleoside-diphosphate reductase subunit M2 (RRM2), that are similarly depleted by XL44 treatment. XL44 induces hRpn13-dependent apoptosis and also restricts cell viability by a PCLAF-dependent mechanism. A KEN box, but not ubiquitination, is required for XL44-induced depletion of PCLAF. Here, we show that XL44 induces ubiquitin-dependent loss of hRpn13Pru and ubiquitin-independent loss of select KEN box containing proteins.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Membrane Glycoproteins / Proteasome Endopeptidase Complex Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Membrane Glycoproteins / Proteasome Endopeptidase Complex Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Type: Article Affiliation country: United States