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dc.contributor.authorJoshi, A
dc.contributor.authorNewbatt, Y
dc.contributor.authorMcAndrew, PC
dc.contributor.authorStubbs, M
dc.contributor.authorBurke, R
dc.contributor.authorRichards, MW
dc.contributor.authorBhatia, C
dc.contributor.authorCaldwell, JJ
dc.contributor.authorMcHardy, T
dc.contributor.authorCollins, I
dc.contributor.authorBayliss, R
dc.date.accessioned2020-07-24T15:07:50Z
dc.date.issued2015-05
dc.identifier.citationOncotarget, 2015, 6 (15), pp. 13019 - 13035
dc.identifier.issn1949-2553
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3872
dc.identifier.eissn1949-2553
dc.identifier.doi10.18632/oncotarget.3864
dc.description.abstractIRE1 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.formatPrint
dc.format.extent13019 - 13035
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectEndoribonucleases
dc.subjectRibonucleases
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectProtein Kinase Inhibitors
dc.subjectLigands
dc.subjectTransfection
dc.subjectProtein Conformation
dc.subjectStructure-Activity Relationship
dc.subjectPhosphorylation
dc.subjectModels, Molecular
dc.subjectProtein Multimerization
dc.subjectDrug Discovery
dc.titleMolecular mechanisms of human IRE1 activation through dimerization and ligand binding.
dc.typeJournal Article
dcterms.dateAccepted2015-03-31
rioxxterms.versionofrecord10.18632/oncotarget.3864
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2015-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncotarget
pubs.issue15
pubs.notesNot 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-statusPublished
pubs.volume6en_US
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 2en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorBurke, Rosemaryen
dc.contributor.icrauthorMcHardy, Tatianaen
dc.contributor.icrauthorCaldwell, Johnen
dc.contributor.icrauthorCollins, Ianen


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