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

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. Schwieters, Marzena A. Dyba, Derek L. Bolhuis, Janusz W. Koscielniak, Thorkell Andresson, Michael J. Emanuele, Nicholas G. Brown, Hiroshi Matsuo, Raj Chari, Deborah E. Citrin, Beverly A. Mock, Rolf E. Swenson and Kylie J. Walters ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46644-7

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