Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands
| Autor: | Breanna Canter, Benjamin T. Walters, Alfred Lammens, Peter Liu, Avi Ashkenazi, Wilson Phung, Weiru Wang, Kevin R Clark, Adrien Le Thomas, Joachim Rudolph, Heidi J.A. Wallweber, Elena Ferri, Eric S. Day, Kyle Mortara, Maureen Beresini, Marie-Gabrielle Braun, Yung-Chia A. Chen, Susan Kaufman |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Folding Protein Conformation RNase P Science Allosteric regulation Endoribonuclease General Physics and Astronomy Kinases Protein Serine-Threonine Kinases Crystallography X-Ray Endoplasmic Reticulum Ligands Article General Biochemistry Genetics and Molecular Biology Stress signalling Gene Knockout Techniques 03 medical and health sciences Adenosine Triphosphate Ribonucleases 0302 clinical medicine Protein structure Endoribonucleases Humans Phosphorylation Protein Kinase Inhibitors X-ray crystallography Multidisciplinary Chemistry Kinase Endoplasmic reticulum Small molecules General Chemistry Cell biology 030104 developmental biology Protein kinase domain 030220 oncology & carcinogenesis Unfolded Protein Response Unfolded protein response Protein Multimerization Allosteric Site |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target. The RNase activity of Inositol-Requiring Enzyme 1 (IRE1) can be allosterically regulated by ATP-competitive inhibitors of the IRE1 kinase domain. Here, the authors identify ATP-competitive IRE1 RNase activators with improved selectivity and cellular activity, and elucidate their mechanism of action. |
| Databáze: | OpenAIRE |
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