dc.contributor.author | Joshi, A | |
dc.contributor.author | Newbatt, Y | |
dc.contributor.author | McAndrew, PC | |
dc.contributor.author | Stubbs, M | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Richards, MW | |
dc.contributor.author | Bhatia, C | |
dc.contributor.author | Caldwell, JJ | |
dc.contributor.author | McHardy, T | |
dc.contributor.author | Collins, I | |
dc.contributor.author | Bayliss, R | |
dc.date.accessioned | 2020-07-24T15:07:50Z | |
dc.date.issued | 2015-05-30 | |
dc.identifier.citation | Oncotarget, 2015, 6 (15), pp. 13019 - 13035 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3872 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.3864 | |
dc.description.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. | |
dc.format | Print | |
dc.format.extent | 13019 - 13035 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Endoribonucleases | |
dc.subject | Ribonucleases | |
dc.subject | Protein-Serine-Threonine Kinases | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Ligands | |
dc.subject | Transfection | |
dc.subject | Protein Conformation | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Phosphorylation | |
dc.subject | Models, Molecular | |
dc.subject | Protein Multimerization | |
dc.subject | Drug Discovery | |
dc.title | Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-03-31 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.3864 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2015-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 15 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.publication-status | Published | |
pubs.volume | 6 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 2 | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Caldwell, John | |
dc.contributor.icrauthor | McHardy, Tatiana | |
dc.contributor.icrauthor | Collins, Ian | |