3LJ0

IRE1 complexed with ADP and Quercetin

Summary for 3LJ0

• Entry DOI: 10.2210/pdb3lj0/pdb
• Related: 3LJ1 3LJ2
• Descriptor: Serine/threonine-protein kinase/endoribonuclease IRE1, MAGNESIUM ION, STRONTIUM ION, ... (5 entities in total)
• Functional Keywords: kinase, flavonol, activator, dimer, atp-binding, endoplasmic reticulum, glycoprotein, hydrolase, magnesium, membrane, metal-binding, multifunctional enzyme, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transcription, transcription regulation, transferase, transmembrane, unfolded protein response
• Biological source: Saccharomyces cerevisiae (yeast)
• Cellular location: Endoplasmic reticulum membrane; Single-pass type I membrane protein: P32361
• Total number of polymer chains: 2
• Total formula weight: 102239.40

Authors

Lee, K.P.K.,Sicheri, F. (deposition date: 2010-01-25, release date: 2010-05-12, Last modification date: 2023-09-06)

Primary citation

Wiseman, R.L.,Zhang, Y.,Lee, K.P.,Harding, H.P.,Haynes, C.M.,Price, J.,Sicheri, F.,Ron, D.
Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1.
Mol.Cell, 38:291-304, 2010

PubMed Abstract: Signaling in the most conserved branch of the endoplasmic reticulum (ER) unfolded protein response (UPR) is initiated by sequence-specific cleavage of the HAC1/XBP1 mRNA by the ER stress-induced kinase-endonuclease IRE1. We have discovered that the flavonol quercetin activates yeast IRE1's RNase and potentiates activation by ADP, a natural activating ligand that engages the IRE1 nucleotide-binding cleft. Enzyme kinetics and the structure of a cocrystal of IRE1 complexed with ADP and quercetin reveal engagement by quercetin of an unanticipated ligand-binding pocket at the dimer interface of IRE1's kinase extension nuclease (KEN) domain. Analytical ultracentrifugation and crosslinking studies support the preeminence of enhanced dimer formation in quercetin's mechanism of action. These findings hint at the existence of endogenous cytoplasmic ligands that may function alongside stress signals from the ER lumen to modulate IRE1 activity and at the potential for the development of drugs that modify UPR signaling from this unanticipated site.

PubMed: 20417606
DOI: 10.1016/j.molcel.2010.04.001

Experimental method

X-RAY DIFFRACTION (3.2 Å)