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A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins

Author

Listed:
  • Xiuxiu Lu

    (National Cancer Institute, National Institutes of Health)

  • Monika Chandravanshi

    (National Cancer Institute, National Institutes of Health)

  • Venkata R. Sabbasani

    (National Institutes of Health)

  • Snehal Gaikwad

    (National Cancer Institute)

  • V. Keith Hughitt

    (National Cancer Institute)

  • Nana Gyabaah-Kessie

    (National Cancer Institute)

  • Bradley T. Scroggins

    (National Cancer Institute, National Institutes of Health)

  • Sudipto Das

    (Inc.)

  • Wazo Myint

    (Frederick National Laboratory for Cancer Research)

  • Michelle E. Clapp

    (Frederick National Laboratory for Cancer Research)

  • Charles D. Schwieters

    (National Institutes of Health)

  • Marzena A. Dyba

    (National Cancer Institute, National Institutes of Health)

  • Derek L. Bolhuis

    (The University of North Carolina at Chapel Hill)

  • Janusz W. Koscielniak

    (National Institutes of Health)

  • Thorkell Andresson

    (Inc.)

  • Michael J. Emanuele

    (The University of North Carolina at Chapel Hill)

  • Nicholas G. Brown

    (The University of North Carolina at Chapel Hill)

  • Hiroshi Matsuo

    (Frederick National Laboratory for Cancer Research)

  • Raj Chari

    (Frederick National Laboratory for Cancer Research)

  • Deborah E. Citrin

    (National Cancer Institute, National Institutes of Health)

  • Beverly A. Mock

    (National Cancer Institute)

  • Rolf E. Swenson

    (National Institutes of Health)

  • Kylie J. Walters

    (National Cancer Institute, National Institutes of Health)

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.

Suggested Citation

  • Xiuxiu Lu & Monika Chandravanshi & Venkata R. Sabbasani & Snehal Gaikwad & V. Keith Hughitt & Nana Gyabaah-Kessie & Bradley T. Scroggins & Sudipto Das & Wazo Myint & Michelle E. Clapp & Charles D. Sch, 2024. "A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46644-7
    DOI: 10.1038/s41467-024-46644-7
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    References listed on IDEAS

    as
    1. Koraljka Husnjak & Suzanne Elsasser & Naixia Zhang & Xiang Chen & Leah Randles & Yuan Shi & Kay Hofmann & Kylie J. Walters & Daniel Finley & Ivan Dikic, 2008. "Proteasome subunit Rpn13 is a novel ubiquitin receptor," Nature, Nature, vol. 453(7194), pages 481-488, May.
    2. Xin Wang & Youn-Sang Jung & Sohee Jun & Sunhye Lee & Wenqi Wang & Andrea Schneider & Young Sun Oh & Steven H. Lin & Bum-Joon Park & Junjie Chen & Khandan Keyomarsi & Jae-Il Park, 2016. "PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    3. Patrick Schreiner & Xiang Chen & Koraljka Husnjak & Leah Randles & Naixia Zhang & Suzanne Elsasser & Daniel Finley & Ivan Dikic & Kylie J. Walters & Michael Groll, 2008. "Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction," Nature, Nature, vol. 453(7194), pages 548-552, May.
    4. Xiuxiu Lu & Venkata R. Sabbasani & Vasty Osei-Amponsa & Christine N. Evans & Julianna C. King & Sergey G. Tarasov & Marzena Dyba & Sudipto Das & King C. Chan & Charles D. Schwieters & Sulbha Choudhari, 2021. "Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
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