4u6r

From Proteopedia

Crystal structure of human IRE1 cytoplasmic domains in complex with a sulfonamide inhibitor.

PDB ID 4u6r

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Structural highlights

4u6r is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ERN1_HUMAN 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 XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.^[1] ^[2] ^[3] [UniProtKB:Q9EQY0]

Publication Abstract from PubMed

The kinase/endonuclease inositol requiring enzyme 1 (IRE1alpha), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1alpha endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1alpha endonuclease as well as cellular IRE1alpha. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1alpha was obtained. Screening of native tumor cell lines (>300) against selective IRE1alpha inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1alpha activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.

Unfolded Protein Response in Cancer: IRE1alpha Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability.,Harrington PE, Biswas K, Malwitz D, Tasker AS, Mohr C, Andrews KL, Dellamaggiore K, Kendall R, Beckmann H, Jaeckel P, Materna-Reichelt S, Allen JR, Lipford JR ACS Med Chem Lett. 2014 Sep 24;6(1):68-72. doi: 10.1021/ml500315b. eCollection, 2015 Jan 8. PMID:25589933^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998 Jun 15;12(12):1812-24. PMID:9637683
↑ Iwawaki T, Hosoda A, Okuda T, Kamigori Y, Nomura-Furuwatari C, Kimata Y, Tsuru A, Kohno K. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat Cell Biol. 2001 Feb;3(2):158-64. PMID:11175748 doi:10.1038/35055065
↑ Liu CY, Xu Z, Kaufman RJ. Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha. J Biol Chem. 2003 May 16;278(20):17680-7. Epub 2003 Mar 13. PMID:12637535 doi:10.1074/jbc.M300418200
↑ Harrington PE, Biswas K, Malwitz D, Tasker AS, Mohr C, Andrews KL, Dellamaggiore K, Kendall R, Beckmann H, Jaeckel P, Materna-Reichelt S, Allen JR, Lipford JR. Unfolded Protein Response in Cancer: IRE1alpha Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability. ACS Med Chem Lett. 2014 Sep 24;6(1):68-72. doi: 10.1021/ml500315b. eCollection, 2015 Jan 8. PMID:25589933 doi:http://dx.doi.org/10.1021/ml500315b