Charlotte Crowe

Induced ubiquitination of the partially disordered Estrogen Receptor alpha protein via a 14-3-3-directed molecular glue-based PROTAC design Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (MGPROTACs) approach that chemically conjugates a molecular glue stabilizer ...

Exciting @biorxivpreprint.bsky.social by the groups of @pjcossar.bsky.social and @alessiociulli.bsky.social. They use a molecular glue between 14-3-3 and an intrinsically disordered domain of ERα to develop a molecular glue-based PROTAC recruiting VHL. doi.org/10.1101/2025...
#TPD #ChemSky #ChemBio

Induced ubiquitination of the partially disordered Estrogen Receptor alpha protein via a 14-3-3-directed molecular glue-based PROTAC design www.biorxiv.org/content/10.1101/2025.11.17.688825v1 #cryoEM

Thank you for sharing @stephanhacker2.bsky.social!

An absolute pleasure to work with all co-authors on this study: from @alessiociulli.bsky.social’s lab (the 🤝 House of VHL 🤝) @alesalerno.bsky.social & Gajanan Sathe – and our wonderful collaboration Graham Marsh and Hannah Maple from Tocris Bio-Techne

We combined cryo-EM, chemical design & synthesis, ternary complex and ubiquitination biophysics & biochemistry, and cellular profiling to tease out the mechanisms at play.

Tuning linker rigidity and length determines whether a ternary complex orientation leads to:
- Efficient substrate ubiquitination & degradation,
- Partial or inefficient ubiquitination,
- Or complete stabilization through a locked, non-productive geometry.

From degradation to stabilisation!

Reprogramming the VHL-degrader CM11 into VHL-stabilisers through linker design, locking a non-ubiquitinable ternary complex.

🔗https://www.biorxiv.org/content/10.1101/2025.11.18.689129v1.full.pdf

Excited to see how this MGPROTAC concept evolves and what new disordered targets we can take on next!

Huge well done to our co-first author Carlo Verhoef and all our fantastic co-investigators Mark Nakasone, Aitana DeLaCuadraBaste, Tessa Harzing, Naomi Span, Gajanan Sathe, Kentaro Iso, Christian Ottmann, Luc Brunsveld and - last but not least @alessiociulli.bsky.social & Peter Cossar

We developed molecular glue-based PROTACs (MGPROTACs) that bring together ERα, 14-3-3 and the VHL E3 ligase in a quaternary complex, mediating ubiquitination on ERα and 14-3-3.

So pleased to contribute some cryo-EM and ubiquitination fun to this study

House of VHL meets house of 14-3-3 🤝

Presenting our study “Induced ubiquitination of the partially disordered Estrogen Receptor alpha protein via a 14-3-3-directed molecular glue-based PROTAC design”

🔗https://www.biorxiv.org/content/10.1101/2025.11.17.688825v1

After the Krios I's 10-year birthday earlier this year (full story can be found here: lnkd.in/eCKF3vBF), it was awesome to visit the eBIC facilities at @diamondlightsource.bsky.social and see that the epic party hat still lives on 🥳

My first 🦋 post! Awesome view over the haar (fog) over the river Tay yesterday afternoon, on the train heading down to
@diamondlightsource.bsky.social for the CCP-EM Icknield workshop - looking forward to a great week of cryo-EM data processing and model building 🔬