4U6R
Crystal structure of human IRE1 cytoplasmic domains in complex with a sulfonamide inhibitor.
Summary for 4U6R
| Entry DOI | 10.2210/pdb4u6r/pdb |
| Related | 4U79 |
| Descriptor | Serine/threonine-protein kinase/endoribonuclease IRE1, N-{4-[(3-{2-[(trans-4-aminocyclohexyl)amino]pyrimidin-4-yl}pyridin-2-yl)oxy]-3-methylnaphthalen-1-yl}-2-chlorobenzenesulfonamide, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | transferase, kinase, hydrolase, endoribonuclease, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Endoplasmic reticulum membrane ; Single-pass type I membrane protein : O75460 |
| Total number of polymer chains | 1 |
| Total formula weight | 53770.46 |
| Authors | Mohr, C. (deposition date: 2014-07-29, release date: 2014-10-08, Last modification date: 2023-09-27) |
| Primary citation | Harrington, P.E.,Biswas, K.,Malwitz, D.,Tasker, A.S.,Mohr, C.,Andrews, K.L.,Dellamaggiore, K.,Kendall, R.,Beckmann, H.,Jaeckel, P.,Materna-Reichelt, S.,Allen, J.R.,Lipford, J.R. Unfolded Protein Response in Cancer: IRE1 alpha Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability. Acs Med.Chem.Lett., 6:68-72, 2015 Cited by PubMed Abstract: The kinase/endonuclease inositol requiring enzyme 1 (IRE1α), 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 IRE1α 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 IRE1α endonuclease as well as cellular IRE1α. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1α was obtained. Screening of native tumor cell lines (>300) against selective IRE1α inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1α 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. PubMed: 25589933DOI: 10.1021/ml500315b PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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