4Z7G

Crystal structure of human IRE1 cytoplasmic kinase-RNase region - apo

Summary for 4Z7G

• Entry DOI: 10.2210/pdb4z7g/pdb
• Descriptor: Serine/threonine-protein kinase/endoribonuclease IRE1, SODIUM ION (3 entities in total)
• Functional Keywords: transferase, kinase, rnase, unfolded protein response
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 95557.62

Authors

Bayliss, R.,Joshi, A. (deposition date: 2015-04-07, release date: 2015-05-27, Last modification date: 2024-01-10)

Primary citation

Joshi, A.,Newbatt, Y.,McAndrew, P.C.,Stubbs, M.,Burke, R.,Richards, M.W.,Bhatia, C.,Caldwell, J.J.,McHardy, T.,Collins, I.,Bayliss, R.
Molecular mechanisms of human IRE1 activation through dimerization and ligand binding.
Oncotarget, 6:13019-13035, 2015

PubMed 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.

PubMed: 25968568
DOI: 10.18632/oncotarget.3864

Experimental method

X-RAY DIFFRACTION (2.6 Å)