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<p>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,&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • 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. Bunker,
  • Kevin J. Lumb,
  • Bernhard Fasching,
  • John C. Castle,
  • Sharon A. Townson,
  • Débora Bonenfant

摘要

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.