Nature Communications (Dec 2021)
Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma
- 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,
- Caroline Fromont,
- Yongmei Zhao,
- Bao Tran,
- Xiang Chen,
- Hiroshi Matsuo,
- Thorkell Andresson,
- Raj Chari,
- Rolf E. Swenson,
- Nadya I. Tarasova,
- Kylie J. Walters
Affiliations
- Xiuxiu Lu
- Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Venkata R. Sabbasani
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health
- Vasty Osei-Amponsa
- Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Christine N. Evans
- Genome Modification Core, Frederick National Laboratory for Cancer Research
- Julianna C. King
- Genome Modification Core, Frederick National Laboratory for Cancer Research
- Sergey G. Tarasov
- Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health
- Marzena Dyba
- Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health
- Sudipto Das
- Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc
- King C. Chan
- Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc
- Charles D. Schwieters
- Computational Biomolecular Magnetic Resonance Core, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
- Sulbha Choudhari
- Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research
- Caroline Fromont
- Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
- Yongmei Zhao
- Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research
- Bao Tran
- Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
- Xiang Chen
- Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Hiroshi Matsuo
- Basic Science Program, Center for Structural Biology, Frederick National Laboratory for Cancer Research
- Thorkell Andresson
- Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc
- Raj Chari
- Genome Modification Core, Frederick National Laboratory for Cancer Research
- Rolf E. Swenson
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health
- Nadya I. Tarasova
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Kylie J. Walters
- Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
- DOI
- https://doi.org/10.1038/s41467-021-27570-4
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 18
Abstract
Rpn13 is a substrate receptor of the 26S proteasome and an anti-cancer drug target. Here, the authors identify and characterize XL5, a lead compound that binds to the N-terminal Pru domain of human Rpn13 (hRpn13), solve the NMR structure of XL5-ligated hRpn13 Pru and develop XL5-PROTACs that preferentially target an identified hRpn13 Pru fragment present in multiple myeloma cells.
