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ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

ABSTRACT: ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

PROVIDER: PRJNA690946 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13394000_1.fastq.gz	Fastqsanger.gz
	SRR13394000_2.fastq.gz	Fastqsanger.gz
	SRR13394001_1.fastq.gz	Fastqsanger.gz
	SRR13394001_2.fastq.gz	Fastqsanger.gz
	SRR13394002_1.fastq.gz	Fastqsanger.gz

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ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

Project description:During mammalian cell growth and differentiation, the unfolded protein response (UPR) homeostatically adjusts endoplasmic reticulum (ER) protein-folding capacity to match changing cellular secretory demands. However, under high/chronic ER stress conditions the UPR triggers apoptosis. This dichotomy is promoted in part by differential activation levels of the ER transmembrane kinase/endoribonuclease (RNase) IRE1a. IRE1a kinase auto-phosphorylation operates as a rheostat to control downstream RNase-induced outputs that either sustain adaptive ER protein-folding or cause apoptosis. We have previously shown that IRE1a’s RNase activity can be activated or fully inactivated by ATP-competitive kinase inhibitors. Here we developed a new class of ATP-competitive kinase inhibitors that partially antagonize the RNase of IRE1a at full occupancy. An atomic level resolution co-crystal structure shows that these small molecule partial antagonists—which we named ‘PAIR’s for (Partial Antagonists of IRE1a RNase)—occupy the ATP-binding site of IRE1a and partially displace a helix (helix aC) in the kinase domain that forms part of a dimeric interface. In insulin-producing beta cells, PAIRs permit adaptive XBP1 mRNA splicing, while quelling destructive/terminal outputs from extra-XBP1 mRNA endonucleolytic decay, thus preventing apoptosis. Preservation of XBP1 splicing by PAIRs permits B lymphocytes to differentiate into immunoglobulin-producing plasma cells. In summary, we propose that an intermediate RNase-inhibitory “sweet spot,” achieved by PAIR-bound IRE1a, may capture a structural conformation naturally available to IRE1a that could represent a desirable therapeutic state for drugging this master UPR sensor/effector.

2021-06-01 | GSE164496 | GEO

ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.

Project description:The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing β-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.

| S-EPMC8551014 | biostudies-literature

Transcriptional profiling of ATP-competitive mTOR inhibitors reveals mTORC1 and mTORC2 specific regulatory networks

Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.

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Transcriptional profiling of ATP-competitive mTOR inhibitors reveals mTORC1 and mTORC2 specific regulatory networks

2011-03-15 | GSE27784 | GEO

GCN2 kinase Activation by ATP-competitive Kinase Inhibitors

Project description:GCN2 kinase Activation by ATP-competitive Kinase Inhibitors

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Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.

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The Oscillating miRNA 959-964 cluster impacts Drosophila feeding time and other circadian outputs.

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2012-11-02 | E-GEOD-40981 | biostudies-arrayexpress

GCN2 kinase Activation by ATP-competitive Kinase Inhibitors

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Competitive RNA Pair Controls Gastric Cancer Metastasis

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