Molecular mechanisms of human IRE1 activation through dimerization and ligand binding.
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ICR Authors
Authors
Joshi, A
Newbatt, Y
McAndrew, PC
Stubbs, M
Burke, R
Richards, MW
Bhatia, C
Caldwell, JJ
McHardy, T
Collins, I
Bayliss, R
Newbatt, Y
McAndrew, PC
Stubbs, M
Burke, R
Richards, MW
Bhatia, C
Caldwell, JJ
McHardy, T
Collins, I
Bayliss, R
Document Type
Journal Article
Date
2015-05-30
Date Accepted
2015-03-31
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.
Citation
Oncotarget, 2015, 6 (15), pp. 13019 - 13035
Source Title
Publisher
IMPACT JOURNALS LLC
ISSN
1949-2553
eISSN
1949-2553
Collections
Research Team
Medicinal Chemistry 2
Hit Discovery & Structural Design
Hit Discovery & Structural Design