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A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

Author

Listed:
  • Gerasimos Langousis

    (Monte Rosa Therapeutics AG)

  • Pablo Gainza

    (Monte Rosa Therapeutics AG)

  • Moritz Hunkeler

    (BioEM Lab, University of Basel)

  • Despoina Kapsitidou

    (Monte Rosa Therapeutics AG)

  • Etienne J. Donckele

    (Monte Rosa Therapeutics AG)

  • Stefano Annunziato

    (Monte Rosa Therapeutics AG)

  • Lars Wiedmer

    (Monte Rosa Therapeutics AG)

  • Katherine F. M. Jones

    (Monte Rosa Therapeutics AG)

  • Bradley DeMarco

    (Monte Rosa Therapeutics AG)

  • Chao Quan

    (Monte Rosa Therapeutics AG)

  • Richard D. Bunker

    (Monte Rosa Therapeutics AG)

  • Kevin J. Lumb

    (Monte Rosa Therapeutics AG)

  • Bernhard Fasching

    (Monte Rosa Therapeutics AG)

  • John C. Castle

    (Monte Rosa Therapeutics AG)

  • Sharon A. Townson

    (Monte Rosa Therapeutics AG)

  • Débora Bonenfant

    (Monte Rosa Therapeutics AG)

Abstract

Cereblon (CRBN) is an E3 ubiquitin ligase widely harnessed for targeted protein degradation (TPD). We report the discovery of a molecular glue degrader (MGD), MRT-31619, that drives homo-dimerization of CRBN and promotes its fast, potent, and selective degradation by the ubiquitin proteasome system. Interestingly, the cryo-electron microscopy (cryo-EM) structure of the CRBN homodimer reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a neosubstrate G-loop degron. This CRBN chemical knockout offers a valuable tool to elucidate the molecular mechanism of MGDs, to investigate its endogenous substrates and understand their physiological roles.

Suggested Citation

  • Gerasimos Langousis & Pablo Gainza & Moritz Hunkeler & Despoina Kapsitidou & Etienne J. Donckele & Stefano Annunziato & Lars Wiedmer & Katherine F. M. Jones & Bradley DeMarco & Chao Quan & Richard D. , 2025. "A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65094-3
    DOI: 10.1038/s41467-025-65094-3
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    References listed on IDEAS

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