dc.contributor.author | Gilburt, JAH | |
dc.contributor.author | Sarkar, H | |
dc.contributor.author | Sheldrake, P | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Ying, L | |
dc.contributor.author | Dodson, CA | |
dc.date.accessioned | 2017-08-16T09:04:18Z | |
dc.date.issued | 2017-09 | |
dc.identifier.citation | Angewandte Chemie (International ed. in English), 2017, 56 (38), pp. 11409 - 11414 | |
dc.identifier.issn | 1433-7851 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/783 | |
dc.identifier.eissn | 1521-3773 | |
dc.identifier.doi | 10.1002/anie.201704654 | |
dc.description.abstract | The 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.format | Print-Electronic | |
dc.format.extent | 11409 - 11414 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Ligands | |
dc.subject | Fluorescence | |
dc.subject | Models, Molecular | |
dc.subject | Aurora Kinase A | |
dc.title | Dynamic Equilibrium of the Aurora A Kinase Activation Loop Revealed by Single-Molecule Spectroscopy. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1002/anie.201704654 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Angewandte Chemie (International ed. in English) | |
pubs.issue | 38 | |
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/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-status | Published | |
pubs.volume | 56 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 1 | |
dc.contributor.icrauthor | Blagg, Julian | |