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TitleChemically-induced degradation of the endoplasmic-reticulum stress sensor IRE1 by a VHL-recruiting chimera.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 11445, Year 2025
Publish dateDec 11, 2025
AuthorsJin Du / Elisia Villemure / Matthew Johnson / Caleigh Azumaya / Catarina J Gaspar / Scot Marsters / David Lawrence / Scott Foster / Alexis Rohou / Tommy K Cheung / Christopher M Rose / Thomas Garner / Soo Ro / Kevin Clark / Maureen H Beresini / Marie-Gabrielle Braun / Joachim Rudolph / Peter Hsu / Avi Ashkenazi /
PubMed AbstractThe 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- ...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.
External linksNat Commun / PubMed:41381506 / PubMed Central
MethodsEM (single particle)
Resolution2.6 Å
Structure data

49119

9n88

EMDB-49119, PDB-9n88:
PROTAC-induced IRE1 ternary complex
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

PDB-1bwf:
ESCHERICHIA COLI GLYCEROL KINASE MUTANT WITH BOUND ATP ANALOG SHOWING SUBSTANTIAL DOMAIN MOTION

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Complex / degrader

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