9OK4

GID4 in complex with CLEO4-88 and ACAA1

This is a non-PDB format compatible entry.

Summary for 9OK4

• Entry DOI: 10.2210/pdb9ok4/pdb
• Descriptor: 3-ketoacyl-CoA thiolase, peroxisomal, Glucose-induced degradation protein 4 homolog, (2S)-2-{[(2S)-2-({N-[(2,4-dimethoxyphenyl)methyl]glycyl}amino)-2-(thiophen-2-yl)acetyl]amino}-N-methyl-4-phenylbutanamide, ... (5 entities in total)
• Functional Keywords: inhibitor, protein complex, molecular glue, thiolase, ctlh complex, e3 ligase, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 128473.61

Authors

Chana, C.K.,Sicheri, F. (deposition date: 2025-05-09, release date: 2026-04-15, Last modification date: 2026-04-22)

Primary citation

Chana, C.K.,Ben Makhlouf, I.,Kim, J.,Yu, A.J.Y.,Moatti, N.,Orlicky, S.,Wong, C.J.,Baronijan, L.,Tang, X.,Mao, D.,Larsen, B.,McGary, L.,Seale, B.,Mader, P.,Ceccarelli, D.F.,Barbulescu, P.,Martin, A.,Durocher, D.,Pelletier, L.,Gingras, A.C.,Sicheri, F.
The molecular glue CLEO4-88 inhibits the ACAA1 thiolase by induced binding to GID4.
Nat.Chem.Biol., 2026

PubMed Abstract: 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 = 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.

PubMed: 41957281
DOI: 10.1038/s41589-026-02183-4

Experimental method

X-RAY DIFFRACTION (2.28 Å)