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<p>Molecular glues promote protein–protein interactions by enhancing the surface complementarity between proteins. Those that recruit an E3 ubiquitin ligase to a target can elicit ubiquitination and subsequent destruction of the target protein—a mechanism that underpins the field of targeted protein degradation (TPD). Here we explored whether small-molecule binders to the CTLH E3 ligase subunit GID4 could act as molecular glues. We discovered that CLEO4-88 functions as a molecular glue (EC<sub>50</sub> = 12.5 nM) to promote the interaction of GID4 with the peroxisomal thiolase ACAA1 in vitro and in cellulo. An atomic structure of the ternary complex revealed an allosteric mechanism whereby CLEO4-88 binds solely to GID4 and induces a conformational change conducive to binding ACAA1. Biochemical analysis demonstrated that, while ACAA1 cannot be recruited by GID4 to a CTLH holoenzyme for ubiquitination, ternary complex formation inhibits ACAA1 thiolase activity, thus demonstrating potential utility beyond TPD.</p><p></p>

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The molecular glue CLEO4-88 inhibits the ACAA1 thiolase by induced binding to GID4

  • 期刊论文

  • 发表日期：

    2026年4月9日

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  • Chetan K. Chana,
  • Ines Ben Makhlouf,
  • Jaeyoun Kim,
  • April J. Y. Yu,
  • Nathalie Moatti,
  • Stephen Orlicky,
  • Cassandra J. Wong,
  • Leon Baronijan,
  • XiaoJing Tang,
  • Daniel Mao,
  • Brett Larsen,
  • Laura McGary,
  • Brendon Seale,
  • Pavel Mader,
  • Derek F. Ceccarelli,
  • Philip Barbulescu,
  • Alberto Martin,
  • Daniel Durocher,
  • Laurence Pelletier,
  • Anne-Claude Gingras,
  • Frank Sicheri

摘要

Molecular glues promote protein–protein interactions by enhancing the surface complementarity between proteins. Those that recruit an E3 ubiquitin ligase to a target can elicit ubiquitination and subsequent destruction of the target protein—a mechanism that underpins the field of targeted protein degradation (TPD). Here we explored whether small-molecule binders to the CTLH E3 ligase subunit GID4 could act as molecular glues. We discovered that CLEO4-88 functions as a molecular glue (EC50 = 12.5 nM) to promote the interaction of GID4 with the peroxisomal thiolase ACAA1 in vitro and in cellulo. An atomic structure of the ternary complex revealed an allosteric mechanism whereby CLEO4-88 binds solely to GID4 and induces a conformational change conducive to binding ACAA1. Biochemical analysis demonstrated that, while ACAA1 cannot be recruited by GID4 to a CTLH holoenzyme for ubiquitination, ternary complex formation inhibits ACAA1 thiolase activity, thus demonstrating potential utility beyond TPD.