Peer-reviewed veterinary case report
A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation.
- Year:
- 2025
- Authors:
- Langousis G et al.
- Affiliation:
- 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.
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Search related cases →Original publication: https://europepmc.org/article/MED/41258141