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

  • Nat Commun. 2025 Nov 19;16(1):10157. doi: 10.1038/s41467-025-65094-3.
Gerasimos Langousis  1 ,  Pablo Gainza  1 ,  Moritz Hunkeler  2 ,  Despoina Kapsitidou  1 ,  Etienne J Donckele  1 ,  Stefano Annunziato  1 ,  Lars Wiedmer  1 ,  Katherine F M Jones  1 ,  Bradley DeMarco  1 ,  Chao Quan  1 ,  Richard D Bunker  1 ,  Kevin J Lumb  1 ,  Bernhard Fasching  1 ,  John C Castle  1 ,  Sharon A Townson  1 ,  Débora Bonenfant  3
Affiliations
  • 1. Monte Rosa Therapeutics AG, Basel, Switzerland.
  • 2. University of Basel, BioEM Lab, Basel, Switzerland.
  • 3. Monte Rosa Therapeutics AG, Basel, Switzerland. [email protected].
PMID: 41258141 DOI: 10.1038/s41467-025-65094-3
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.

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