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TitleCharged molecular glue discovery enabled by targeted degron display.
Journal, issue, pagesNat Chem Biol, Year 2026
Publish dateApr 6, 2026
AuthorsZhe Zhuang / Woong Sub Byun / Jakub Chrustowicz / Zuzanna Kozicka / Veronica L Li / Dinah M Abeja / Katherine A Donovan / Sara Sepic / Inchul You / Mikołaj Słabicki / Eric S Fischer / Stephen M Hinshaw / Benjamin L Ebert / Brenda A Schulman / Nathanael S Gray /
PubMed AbstractSmall molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation ...Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity-inducing molecules, especially molecular glue degraders (MGDs). These compounds catalyze the destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. MGD discovery for predefined targets is a major challenge in contemporary drug discovery. Here, we solve this important chemical challenge through 'chemocentric' MGD discovery of ZZ1, a BET-family protein degrader and a prodrug of a negatively charged glue. ZZ1 activation unmasks a sulfinic acid that binds the modular CTLH ubiquitin ligase complex through a basic pocket in its YPEL5 subunit. These findings demonstrate a previously unrecognized capacity of YPEL5 to recruit CTLH substrates and enable the discovery of MGDs for exceedingly common acidic and basic degrons.
External linksNat Chem Biol / PubMed:41942733
MethodsEM (single particle)
Resolution3.38 - 11.77 Å
Structure data

EMDB-54194: ZZ1-SO2H-induced assembly of the YPEL5-CTLH E3 ligase and BRD4(BD1) neosubstrate
Method: EM (single particle) / Resolution: 11.77 Å

54215

9rsc

EMDB-54215, PDB-9rsc:
Ternary complex of an improved charged molecular glue degrader ZZ2-SO2H, BRD4(BD1) neosubstrate, and the CTLH E3 ligase receptor module YPEL5-WDR26
Method: EM (single particle) / Resolution: 3.42 Å

54216

9rsd

EMDB-54216, PDB-9rsd:
Ternary complex of a charged molecular glue degrader ZZ1-SO2H, BRD4(BD1) neosubstrate, and the CTLH E3 ligase receptor module YPEL5-WDR26
Method: EM (single particle) / Resolution: 3.38 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1il8:
THREE-DIMENSIONAL STRUCTURE OF INTERLEUKIN 8 IN SOLUTION

ChemComp-HOH:
WATER

PDB-1il9:
STRUCTURE OF RICIN A CHAIN BOUND WITH INHIBITOR 8-METHYL-9-OXOGUANINE

Source
  • homo sapiens (human)
KeywordsLIGASE / E3 ubiquitin ligase / CTLH / GID / YPEL5 / Molecular Glue Degrader / Targeted Protein Degradation

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