4Z7H

Crystal structure of human IRE1 cytoplasmic kinase-RNase region - complex with imidazopyridine compound 3

4Z7H の概要

• エントリーDOI: 10.2210/pdb4z7h/pdb
• 分子名称: Serine/threonine-protein kinase/endoribonuclease IRE1, 2-methoxy-4-[6-(propan-2-ylamino)imidazo[1,2-b]pyridazin-3-yl]benzamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: transferase, kinase, rnase, unfolded protein response
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96258.43

構造登録者

Joshi, A.,Bayliss, R. (登録日: 2015-04-07, 公開日: 2015-05-27, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.9 Å)