9N88

PROTAC-induced IRE1 ternary complex

This is a non-PDB format compatible entry.

Summary for 9N88

• Entry DOI: 10.2210/pdb9n88/pdb
• EMDB information: 49119
• Descriptor: Serine/threonine-protein kinase/endoribonuclease IRE1, von Hippel-Lindau disease tumor suppressor, Elongin-C, ... (6 entities in total)
• Functional Keywords: complex, degrader, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 151017.49

Authors

Du, J.,Johnson, M.,Azumaya, C.,Rohou, A.,Hsu, P.L.,Ashkenazi, A. (deposition date: 2025-02-07, release date: 2025-11-05, Last modification date: 2026-04-22)

Primary citation

Du, J.,Villemure, E.,Johnson, M.,Azumaya, C.,Gaspar, C.J.,Marsters, S.,Lawrence, D.,Foster, S.,Rohou, A.,Cheung, T.K.,Rose, C.M.,Garner, T.,Ro, S.,Clark, K.,Beresini, M.H.,Braun, M.G.,Rudolph, J.,Hsu, P.,Ashkenazi, A.
Chemically-induced degradation of the endoplasmic-reticulum stress sensor IRE1 by a VHL-recruiting chimera.
Nat Commun, 16:11445-11445, 2025

PubMed Abstract: The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-endoribonuclease and scaffolding activities. Cancer cells often co-opt IRE1 to facilitate growth. An IRE1-RNase inhibitor has entered clinical trials; however, recent work uncovered a significant nonenzymatic IRE1 dependency in cancer. To fully disrupt IRE1, we describe a proteolysis-targeting chimera (G6374) that couples an IRE1-kinase ligand to a compound that binds the ubiquitin Cullin-RING Ligase (CRL) substrate receptor, VHL. G6374 induces a stable, cooperative interaction between IRE1 and VHL, driving K48-linked ubiquitination on two principal lysine residues in the IRE1-kinase domain and inducing proteasomal IRE1 degradation. Cryogenic electron microscopy and mutagenesis studies reveal a 2:2 IRE1:VHL ternary-complex topology and critical interactional features, informing future designs. G6374 blocks growth of IRE1-dependent cancer cells irrespective of their dependency mode, while sparing IRE1-independent cells. We provide a proof-of-concept for VHL-based degradation of an ER-transmembrane protein, advancing strategies to fully disrupt IRE1.

PubMed: 41381506
DOI: 10.1038/s41467-025-66382-8

Experimental method

ELECTRON MICROSCOPY (2.6 Å)