Diamond Publications - Search Results

Search Again...

These results include publications that have not yet been reviewed and processed by Diamond Light Source. To view only processed publications click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

One item found (0 items not approved).

Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	Molecular mechanisms of human IRE1 activation through dimerization and ligand binding Amar Joshi , Yvette Newbatt , P. Craig Mcandrew , Mark Stubbs , Rosemary Burke , Mark Richards , Chitra Bhatia , John J. Caldwell , Tatiana Mchardy , Ian Collins , Richard Bayliss Oncotarget 6, 13019 - 13035 DOI: 10.18632/oncotarget.3864 Diamond Proposal Number(s): [10369] Open Access Show Abstract ▼ 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.	Apr 2015

Instruments / Technical Area

Publication Details

Published

Actions

I04-1-Macromolecular Crystallography (fixed wavelength)

Molecular mechanisms of human IRE1 activation through dimerization and ligand binding