3lj2

IRE1 complexed with JAK Inhibitor I

spinqualitylabelsall models 3lj2, resolution 3.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3lj2 is a 2 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: IZA NonStd Res: SEP, TPO Related: 3lj0, 3lj1 Gene: ERN1, IRE1, YHR079C (Saccharomyces cerevisiae) Resources: FirstGlance, OCA, RCSB, PDBsum Function [IRE1_YEAST] Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices HAC1 precursor mRNA to produce the mature form which then induces transcription of UPR target genes. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1.,Wiseman RL, Zhang Y, Lee KP, Harding HP, Haynes CM, Price J, Sicheri F, Ron D Mol Cell. 2010 Apr 23;38(2):291-304. PMID:20417606 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ire1

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