Skip NavigationSkip to Content
Return Return to Search Results

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

  1. Author:
    Lu, Xiuxiu
    Sabbasani, Venkata R.
    Osei-Amponsa, Vasty
    Evans, Christine N.
    King, Julianna C.
    Tarasov, Sergey G.
    Dyba, Marzena
    Das, Sudipto
    Chan, King C.
    Schwieters, Charles D.
    Choudhari, Sulbha
    Fromont, Caroline
    Zhao, Yongmei
    Tran, Bao
    Chen, Xiang
    Matsuo, Hiroshi
    Andresson, Thorkell
    Chari, Raj
    Swenson, Rolf E.
    Tarasova, Nadya I.
    Walters, Kylie J.

  2. Author Address

    NCI, NIH, Ctr Canc Res, Prot Proc Sect,Ctr Struct Biol, Frederick, MD 21702 USA.NHLBI, NIH, Chem & Synth Ctr, Bethesda, MD 20892 USA.Frederick Natl Lab Canc Res, Genome Modificat Core, Frederick, MD 21702 USA.NCI, NIH, Struct Biol Ctr, Biophys Resource, Frederick, MD 21702 USA.Leidos Biomed Res Inc, Prot Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.NIDDK, NIH, Chem Phys Lab, Computat Biomol Magnet Resonance Core, Bethesda, MD 20892 USA.Frederick Lab Canc Res, Sequencing Facil Bioinformat Grp, Biomed Informat & Data Sci Directorate, Frederick, MD 21701 USA.Frederick Natl Lab Canc Res, Sequencing Facil Canc Res Technol Program, Frederick, MD 21701 USA.Frederick Natl Lab Canc Res, Basic Sci Program, Struct Biol Ctr, Frederick, MD 21702 USA.NCI, NIH, Lab Canc Immunometab, Ctr Canc Res, Frederick, MD 21702 USA.
    1. Year: 2021
    2. Date: Dec 16
  2. Journal: Nature Communications
  3. Nature Portfolio
    1. 12
    2. 1
  5. Type of Article: Article
  6. Article Number: ARTN 7318
  7. ISSN: 2041-1723
  1. 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 beta-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13(Pru)) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13(Pru), 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 hRpn13(Pru)-producing cancer types.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1038/s41467-021-27570-4
  3. PMID: 34916494
  4. View record in Web of Science®
  5. WOS: 000731101200016

Library Notes

  1. Fiscal Year: FY2021-2022
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel