9SV3

Local refinement of EloB/EloC/VHL/CV2a/14-3-3zeta/ERa from pose 1

This is a non-PDB format compatible entry.

Summary for 9SV3

• Entry DOI: 10.2210/pdb9sv3/pdb
• EMDB information: 55233
• Descriptor: Elongin-C, Elongin-B, Estrogen receptor, ... (6 entities in total)
• Functional Keywords: e3 ligase, von hippel-lindau, vhl, 14-3-3, estrogen receptor alpha, protac, proteolysis targeting chimera, degrader, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 191320.79

Authors

Crowe, C.,Nakasone, M.A.,Harzing, T.,Verhoef, C.J.A.,Cossar, P.J.,Ciulli, A. (deposition date: 2025-09-30, release date: 2025-12-03, Last modification date: 2026-07-29)

Primary citation

Verhoef, C.J.A.,Crowe, C.,Nakasone, M.A.,DeLaCuadra-Baste, A.,Harzing, T.,Span, N.A.S.,Sathe, G.,Demmers, L.C.,Iso, K.,Ottmann, C.,Brunsveld, L.,Ciulli, A.,Cossar, P.J.
Induced ubiquitination of the partially disordered estrogen receptor alpha via a 14-3-3 directed molecular glue-PROTAC.
Nat Commun, 2026

PubMed Abstract: 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.

PubMed: 42457718
DOI: 10.1038/s41467-026-75333-w

Experimental method

ELECTRON MICROSCOPY (4.3 Å)