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dc.contributor.authorGilburt, JAH
dc.contributor.authorSarkar, H
dc.contributor.authorSheldrake, P
dc.contributor.authorBlagg, J
dc.contributor.authorYing, L
dc.contributor.authorDodson, CA
dc.date.accessioned2017-08-16T09:04:18Z
dc.date.issued2017-09
dc.identifier.citationAngewandte Chemie (International ed. in English), 2017, 56 (38), pp. 11409 - 11414
dc.identifier.issn1433-7851
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/783
dc.identifier.eissn1521-3773
dc.identifier.doi10.1002/anie.201704654
dc.description.abstractThe conformation of the activation loop (T-loop) of protein kinases underlies enzymatic activity and influences the binding of small-molecule inhibitors. By using single-molecule fluorescence spectroscopy, we have determined that phosphorylated Aurora A kinase is in dynamic equilibrium between a DFG-in-like active T-loop conformation and a DFG-out-like inactive conformation, and have measured the rate constants of interconversion. Addition of the Aurora A activating protein TPX2 shifts the equilibrium towards an active T-loop conformation whereas addition of the inhibitors MLN8054 and CD532 favors an inactive T-loop. We show that Aurora A binds TPX2 and MLN8054 simultaneously and provide a new model for kinase conformational behavior. Our approach will enable conformation-specific effects to be integrated into inhibitor discovery across the kinome, and we outline some immediate consequences for structure-based drug discovery.
dc.formatPrint-Electronic
dc.format.extent11409 - 11414
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectProtein Kinase Inhibitors
dc.subjectLigands
dc.subjectFluorescence
dc.subjectModels, Molecular
dc.subjectAurora Kinase A
dc.titleDynamic Equilibrium of the Aurora A Kinase Activation Loop Revealed by Single-Molecule Spectroscopy.
dc.typeJournal Article
rioxxterms.versionofrecord10.1002/anie.201704654
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAngewandte Chemie (International ed. in English)
pubs.issue38
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/Medicinal Chemistry 1
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/Medicinal Chemistry 1
pubs.publication-statusPublished
pubs.volume56
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 1en_US
dc.contributor.icrauthorBlagg, Julian


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