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TitleEnzyme-Activated Sugar-Coated Bifunctional Degraders.
Journal, issue, pagesJ Am Chem Soc, Vol. 147, Issue 38, Page 34672-34680, Year 2025
Publish dateSep 24, 2025
AuthorsQian Zhu / Gerhard Fischer / Steven S Cheng / N Connor Payne / Daniel Peter / Alison C Mody / Silvia Arce-Solano / Dacheng Shen / Zhi Lin / Ralph Mazitschek / Dirk Kessler / Christina M Woo /
PubMed AbstractTargeted protein degradation with compounds like proteolysis targeting chimeras (PROTACs) directs disease-associated proteins to the E3 ligase ubiquitin-proteasome system for removal. However, ...Targeted protein degradation with compounds like proteolysis targeting chimeras (PROTACs) directs disease-associated proteins to the E3 ligase ubiquitin-proteasome system for removal. However, commonly employed E3 ligases such as cereblon (CRBN) are broadly expressed. To metabolically gate PROTAC activity, we developed an enzymatic activation strategy by integrating an O-GlcNAc modification to the cyclimids, ligands derived from the natural motifs recognized by CRBN. These sugar-coated PROTACs (SCPs) were designed using structural analyses of representative cyclimid degraders complexed with CRBN and target protein BRD4. We found that glycosylation of the cyclimid reduced CRBN binding and complex formation with BRD4 until enzymatic removal of the O-GlcNAc moiety by O-GlcNAcase (OGA). The requirement for enzymatic activation is demonstrated by biochemical binding, cellular degradation, and cell viability assays in engineered and native cell lines. O-GlcNAc is thus an effective mechanism to gate targeted protein degradation modalities that motivates the development of similar strategies to enhance selectivity with other protein modifications.
External linksJ Am Chem Soc / PubMed:40937862
MethodsEM (single particle)
Resolution2.55 - 2.85 Å
Structure data

54690

9saf

EMDB-54690, PDB-9saf:
Ternary PROTAC-mediated complex of BRD4-BD1/CRBN/DDB1 and JQ1-AcQ bifunctional degrader
Method: EM (single particle) / Resolution: 2.55 Å

54691

9sai

EMDB-54691, PDB-9sai:
Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN
Method: EM (single particle) / Resolution: 2.66 Å

EMDB-54895: Focus map of ternary PROTAC-mediated complex of BRD4-BD1/CRBN/DDB1 and JQ1-AcQ bifunctional degrader
Method: EM (single particle) / Resolution: 2.85 Å

EMDB-54896: Consensus map of ternary PROTAC-mediated complex of BRD4-BD1/CRBN/DDB1 and JQ1-AcQ bifunctional degrader
Method: EM (single particle) / Resolution: 2.55 Å

Chemicals

ChemComp-ZN:
Unknown entry


PDB Unreleased entry

PDB-1jm8: PURINE REPRESSOR MUTANT-GUANINE-PURF OPERATOR COMPLEX

ChemComp-HOH:
WATER

PDB-1jm3:
Unknown entry

Source
  • homo sapiens (human)
KeywordsLIGASE / Cryo-EM DDB1 (DNA Damage-Binding Protein 1) CRBN (Cereblon) BRD4 (bromodomain containing 4) Protein degradation cyclimid PROTACs / ternary complex / PROTAC / cereblon

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