4z7h | pdb_00004z7h

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

spinqualitylabelsall models 4z7h, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4z7h is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4L5, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ERN1_HUMAN] Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis. [UniProtKB:Q9EQY0] Publication Abstract from PubMed 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. Molecular mechanisms of human IRE1 activation through dimerization and ligand binding.,Joshi A, Newbatt Y, McAndrew PC, Stubbs M, Burke R, Richards MW, Bhatia C, Caldwell JJ, McHardy T, Collins I, Bayliss R Oncotarget. 2015 Apr 18. PMID:25968568 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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