A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41258141.
- Also identified by DOI 10.1038/s41467-025-65094-3 and PMC identifier 12630686.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Ubiquitin-Protein Ligases
- Adaptor Proteins, Signal Transducing
- Protein Multimerization