Molecular mechanisms of human IRE1 activation through dimerization and ligand binding
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Amar Joshi1,2, Yvette Newbatt3, P. Craig McAndrew3, Mark Stubbs3, Rosemary Burke3, Mark W. Richards1,2, Chitra Bhatia1,2, John J. Caldwell3, Tatiana McHardy3, Ian Collins3 and Richard Bayliss1,2
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
Richard Bayliss, email:
Ian Collins, email:
Keywords: UPR, drug discovery, kinase, RNase
Received: December 02, 2014 Accepted: March 31, 2015 Published: April 18, 2015
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.
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