A Covalent Cysteine-Targeting Kinase Inhibitor of Ire1 Permits Allosteric Control of Endoribonuclease Activity
| Autor: | Youla S. Tsantrizos, Kurt Dejgaard, Lekha Sleno, David Y. Thomas, Daniel D Waller, René Roy, Tze Chieh Shiao, Gregor Jansen, Makan Golizeh, Michael Sebag, Chloe Martel-Lorion, John Mancuso |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Saccharomyces cerevisiae Proteins Endoribonuclease activity Allosteric regulation Molecular Sequence Data Pyrimidinones Saccharomyces cerevisiae Biology Protein Serine-Threonine Kinases Biochemistry 03 medical and health sciences Allosteric Regulation Endoribonucleases medicine Humans Amino Acid Sequence Cysteine Molecular Biology Protein Kinase Inhibitors Kinase Organic Chemistry Rational design Transmembrane protein 030104 developmental biology Mechanism of action Unfolded protein response Biocatalysis Mutagenesis Site-Directed Unfolded Protein Response Molecular Medicine medicine.symptom Sequence Alignment |
| Zdroj: | Chembiochem : a European journal of chemical biology. 17(9) |
| ISSN: | 1439-7633 |
| Popis: | The unfolded protein response (UPR) initiated by the transmembrane kinase/ribonuclease Ire1 has been implicated in a variety of diseases. Ire1, with its unique position in the UPR, is an ideal target for the development of therapies; however, the identification of specific kinase inhibitors is challenging. Recently, the development of covalent inhibitors has gained great momentum because of the irreversible deactivation of the target. We identified and determined the mechanism of action of the Ire1-inhibitory compound UPRM8. MS analysis revealed that UPRM8 inhibition occurs by covalent adduct formation at a conserved cysteine at the regulatory DFG+2 position in the Ire1 kinase activation loop. Mutational analysis of the target cysteine residue identified both UPRM8-resistant and catalytically inactive Ire1 mutants. We describe a novel covalent inhibition mechanism of UPRM8, which can serve as a lead for the rational design and optimization of inhibitors of human Ire1. |
| Databáze: | OpenAIRE |
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