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TitleA degron-mimicking molecular glue drives CRBN homo-dimerization and degradation.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 10157, Year 2025
Publish dateNov 19, 2025
AuthorsGerasimos Langousis / Pablo Gainza / Moritz Hunkeler / Despoina Kapsitidou / Etienne J Donckele / Stefano Annunziato / Lars Wiedmer / Katherine F M Jones / Bradley DeMarco / Chao Quan / Richard D Bunker / Kevin J Lumb / Bernhard Fasching / John C Castle / Sharon A Townson / Débora Bonenfant /
PubMed AbstractCereblon (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 ...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.
External linksNat Commun / PubMed:41258141 / PubMed Central
MethodsEM (single particle)
Resolution2.93 - 3.1 Å
Structure data

52330

9hpi

EMDB-52330, PDB-9hpi:
Cryo-EM structure of DDB1dB-CRBN-MRT-0031619, conformation 1
Method: EM (single particle) / Resolution: 2.93 Å

52331

9hpj

EMDB-52331, PDB-9hpj:
Cryo-EM structure of DDB1dB-CRBN-MRT-0031619, conformation 2
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1iw1:
Crystal structure of a heme oxygenase (HmuO) from Corynebacterium diphtheriae complexed with heme in the ferrous state

Source
  • homo sapiens (human)
KeywordsLIGASE / Targeted protein degradation / molecular glue / ubiquitin proteasome system / CRBN / ubiquitin ligase

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