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Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma

Author

Listed:
  • Xiuxiu Lu

    (National Institutes of Health)

  • Venkata R. Sabbasani

    (National Institutes of Health)

  • Vasty Osei-Amponsa

    (National Institutes of Health)

  • Christine N. Evans

    (Frederick National Laboratory for Cancer Research)

  • Julianna C. King

    (Frederick National Laboratory for Cancer Research)

  • Sergey G. Tarasov

    (National Institutes of Health)

  • Marzena Dyba

    (National Institutes of Health)

  • Sudipto Das

    (Leidos Biomedical Research, Inc)

  • King C. Chan

    (Leidos Biomedical Research, Inc)

  • Charles D. Schwieters

    (National Institutes of Health)

  • Sulbha Choudhari

    (Frederick National Laboratory for Cancer Research)

  • Caroline Fromont

    (Frederick National Laboratory for Cancer Research)

  • Yongmei Zhao

    (Frederick National Laboratory for Cancer Research)

  • Bao Tran

    (Frederick National Laboratory for Cancer Research)

  • Xiang Chen

    (National Institutes of Health)

  • Hiroshi Matsuo

    (Frederick National Laboratory for Cancer Research)

  • Thorkell Andresson

    (Leidos Biomedical Research, Inc)

  • Raj Chari

    (Frederick National Laboratory for Cancer Research)

  • Rolf E. Swenson

    (National Institutes of Health)

  • Nadya I. Tarasova

    (National Institutes of Health)

  • Kylie J. Walters

    (National Institutes of Health)

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 (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.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27570-4
    DOI: 10.1038/s41467-021-27570-4
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    References listed on IDEAS

    as
    1. 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.
    2. 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.
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    Cited by:

    1. 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.

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