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TitleInduced ubiquitination of the partially disordered estrogen receptor alpha via a 14-3-3 directed molecular glue-PROTAC.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJul 15, 2026
AuthorsCarlo J A Verhoef / Charlotte Crowe / Mark A Nakasone / Aitana DeLaCuadra-Basté / Tessa Harzing / Naomi A S Span / Gajanan Sathe / Laura C Demmers / Kentaro Iso / Christian Ottmann / Luc Brunsveld / Alessio Ciulli / Peter J Cossar /
PubMed AbstractProteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (PROTAC) approach that chemically conjugates a molecular glue stabilizer to ...Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (PROTAC) approach that chemically conjugates a molecular glue stabilizer to a VHL-recruiting ligand to capture and ubiquitinate the 14-3-3/Estrogen receptor α (ERα) complex. Our designed PROTACs engage a composite interface between 14-3-3 and the disordered F-domain of ERα, promoting cooperative complex formation and targeted ubiquitination. Biophysical characterization revealed distinct linker-dependent cooperativities across the PROTAC series, which influenced both cellular permeability and ubiquitination efficiency. Cryo-EM of the most cooperative PROTAC uncovered de novo VHL-14-3-3ζ contacts, while molecular dynamics simulations rationalize the stabilizing interactions underlying cooperativity. Strikingly, fine-tuning linker design enables selective ubiquitination of distinct complex subunits. These findings establish a structural and mechanistic framework for integrating molecular glue and PROTAC principles, expanding the scope of drug discovery to previously intractable protein complexes.
External linksNat Commun / PubMed:42457718
MethodsEM (single particle)
Resolution4.3 - 6.5 Å
Structure data

55233

9sv3

EMDB-55233, PDB-9sv3:
Local refinement of EloB/EloC/VHL/CV2a/14-3-3zeta/ERa from pose 1
Method: EM (single particle) / Resolution: 4.3 Å

EMDB-55234: EloB/EloC/VHL/CV2a/14-3-3zeta/ERa pose 1
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-55235: EloB/EloC/VHL/CV2a/14-3-3zeta/ERa pose 2.1
Method: EM (single particle) / Resolution: 6.5 Å

EMDB-55236: EloB/EloC/VHL/CV2a/14-3-3zeta/ERa pose 2.2
Method: EM (single particle) / Resolution: 6.0 Å

EMDB-55237: EloB/EloC/VHL/CV2a/14-3-3zeta/ERa pose 3
Method: EM (single particle) / Resolution: 5.6 Å

Chemicals

PDB-1jqt:
Fitting of L11 protein in the low resolution cryo-EM map of E.coli 70S ribosome

Source
  • homo sapiens (human)
KeywordsLIGASE / E3 ligase / von Hippel-Lindau / VHL / 14-3-3 / estrogen receptor alpha / PROTAC / proteolysis targeting chimera / degrader

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