4U6R

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

4U6R の概要

• エントリーDOI: 10.2210/pdb4u6r/pdb
• 関連するPDBエントリー: 4U79
• 分子名称: 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)
• 機能のキーワード: transferase, kinase, hydrolase, endoribonuclease, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Single-pass type I membrane protein : O75460
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53770.46

構造登録者

Mohr, C. (登録日: 2014-07-29, 公開日: 2014-10-08, 最終更新日: 2023-09-27)

主引用文献

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

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: 25589933
DOI: 10.1021/ml500315b

実験手法

X-RAY DIFFRACTION (2.5 Å)