Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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, 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
doi: https://doi.org/10.1101/2021.07.16.452547
Xiuxiu Lu
1Protein Processing Section, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Venkata R. Sabbasani
2Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vasty Osei-Amponsa
1Protein Processing Section, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christine N. Evans
3Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julianna C. King
3Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sergey G. Tarasov
4Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marzena Dyba
4Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
King C. Chan
5Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles D. Schwieters
6Computational Biomolecular Magnetic Resonance Core, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-5620, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sulbha Choudhari
7Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Caroline Fromont
8Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yongmei Zhao
7Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bao Tran
8Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiang Chen
1Protein Processing Section, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroshi Matsuo
9Basic Science Program, Center for Structural Biology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thorkell Andresson
5Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raj Chari
3Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rolf E. Swenson
2Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nadya I. Tarasova
10Cancer Immunometabolism Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kylie J. Walters
1Protein Processing Section, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: kylie.walters@nih.gov
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

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 and increased p62 levels. 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted July 17, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
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, 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
bioRxiv 2021.07.16.452547; doi: https://doi.org/10.1101/2021.07.16.452547
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
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, 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
bioRxiv 2021.07.16.452547; doi: https://doi.org/10.1101/2021.07.16.452547

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Molecular Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3686)
  • Biochemistry (7766)
  • Bioengineering (5664)
  • Bioinformatics (21228)
  • Biophysics (10551)
  • Cancer Biology (8156)
  • Cell Biology (11901)
  • Clinical Trials (138)
  • Developmental Biology (6733)
  • Ecology (10387)
  • Epidemiology (2065)
  • Evolutionary Biology (13836)
  • Genetics (9691)
  • Genomics (13051)
  • Immunology (8119)
  • Microbiology (19929)
  • Molecular Biology (7823)
  • Neuroscience (42947)
  • Paleontology (318)
  • Pathology (1276)
  • Pharmacology and Toxicology (2256)
  • Physiology (3349)
  • Plant Biology (7207)
  • Scientific Communication and Education (1309)
  • Synthetic Biology (1998)
  • Systems Biology (5527)
  • Zoology (1126)