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Molecular mechanisms of human IRE1 activation through dimerization and ligand binding

DOI: 10.18632/oncotarget.3864 DOI Help

Authors: Amar Joshi (University of Leicester) , Yvette Newbatt (Cancer Research UK) , P. Craig Mcandrew (Cancer Research UK) , Mark Stubbs (Cancer Research UK) , Rosemary Burke (Cancer Research UK) , Mark Richards (University of Leicester) , Chitra Bhatia (University of Leicester) , John J. Caldwell (Cancer Research UK) , Tatiana Mchardy (Cancer Research UK) , Ian Collins (Cancer Research UK) , Richard Bayliss (University of Leicester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Oncotarget , VOL 6 , PAGES 13019 - 13035

State: Published (Approved)
Published: April 2015
Diamond Proposal Number(s): 10369

Open Access Open Access

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.

Journal Keywords: UPR; Drug Discovery; Kinase; Rnase

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)