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• W1907956523 abstract "// Amar Joshi 1,2 , Yvette Newbatt 3 , P. Craig McAndrew 3 , Mark Stubbs 3 , Rosemary Burke 3 , Mark W. Richards 1,2 , Chitra Bhatia 1,2 , John J. Caldwell 3 , Tatiana McHardy 3 , Ian Collins 3 and Richard Bayliss 1,2 1 Department of Biochemistry, University of Leicester, Leicester, United Kingdom 2 Cancer Research UK Leicester Centre, University of Leicester, Leicester, United Kingdom 3 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom Correspondence to: Richard Bayliss, email: // Ian Collins, email: // Keywords : UPR, drug discovery, kinase, RNase Received : December 02, 2014 Accepted : March 31, 2015 Published : April 18, 2015 Abstract IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures. We have crystallized human IRE1 in a back-to-back conformation only previously seen for the yeast homologue. In our structure the kinase domain appears primed for catalysis but the RNase domains are disengaged. Structure-function analysis reveals that IRE1 is autoinhibited through a Tyr-down mechanism related to that found in the unrelated Ser/Thr protein kinase Nek7. We have developed a compound that potently inhibits human IRE1 kinase activity while stimulating XBP1 splicing. A crystal structure of the inhibitor bound to IRE1 shows an increased ordering of the kinase activation loop. The structures of hIRE in apo and ligand-bound forms are consistent with a previously proposed model of IRE1 regulation in which formation of a back-to-back dimer coupled to adoption of a kinase-active conformation drive RNase activation. The structures provide opportunities for structure-guided design of IRE1 inhibitors." @default.
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• W1907956523 date "2015-04-18" @default.
• W1907956523 modified "2023-10-17" @default.
• W1907956523 title "Molecular mechanisms of human IRE1 activation through dimerization and ligand binding" @default.
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• W1907956523 doi "https://doi.org/10.18632/oncotarget.3864" @default.
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