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Overview
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Background
APY29 is an inhibitor of IRE1α with IC50 value of 0.28μM [1].IRE1α is a transmembrane protein in ER. It can be activated when unfolded proteins accumulate in ER. APY29 is found to interact with the ATP-binding site of wild-type IRE1α and activate the kinase activity of IRE1α even without upstream ER stress. APY29 acts as a slight activator and stabilizes IRE1α’s kinase domain in an alternative conformation. It is found to restore the ability of dephosphorylated IRE1α to cleave the substrate XBP1 up to about 60% of the levels of normal IRE1α. Furthermore, APY29 increases the oligomer/monomer ratio of IRE1α and finally displays a decrease of IRE1α trans-autophosphorylation [1].
[1] Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schürer SC, Oakes SA, Papa FR, Maly DJ. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat Chem Biol. 2012 Dec;8(12):982-9.
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