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.

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